NEUROMODULATING COMPOSITIONS AND RELATED THERAPEUTIC METHODS FOR THE

TREATMENT OF CANCER

BACKGROUND

Cancer is still one of the deadliest threats to human health. In 2012, there were 14 million new cases of cancer worldwide and 8.2 million cancer-related deaths. The number of new cancer cases is expected to rise to 22 million by 2030, and worldwide cancer deaths are project to increase by 60%. Thus, there remains a need in the field for treatments for cancer. SUMMARY OF THE INVENTION

The invention relates to the discovery that modulation of neurological signaling pathways can modulate cellular responses in cancer cells and, e.g., can be used to treat cancer. Accordingly, therapeutic and pharmaceutical compositions (as well as veterinary compositions) comprising neuromodulating agents and related methods are disclosed herein for treatment of cancer. The invention also features methods of profiling, categorizing, and selecting treatment for a subject based on neurome gene expression in a tumor or cancer cell.

In one aspect, the invention provides a method of treating a subject with cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject identified as having cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject with cancer by contacting a tumor or cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject identified as having cancer by contacting a tumor or cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject at risk of developing cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject identified as at risk of developing cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments of any of the above aspects, the cancer is pancreatic cancer and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is small cell lung cancer (SCLC) and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is melanoma and the method includes administering to the subject an effective amount of a

neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is prostate cancer and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is breast cancer and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is glioma and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator. In some embodiments, the cancer is gastric cancer and the method includes administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing tumor growth by contacting a tumor with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing tumor growth by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing tumor volume by contacting a tumor with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing tumor volume by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing the number or activity of nerve fibers in a tumor or tumor microenvironment by contacting a tumor or tumor microenvironment with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing the number or activity of nerve fibers in a tumor or tumor microenvironment by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In some embodiments of any of the above aspects, the tumor is highly innervated.

In another aspect, the invention provides a method of decreasing cancer cell proliferation by contacting a cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing cancer cell proliferation by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing cancer cell metastasis by contacting a cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing cancer cell metastasis by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing cancer cell invasion by contacting a cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing cancer cell invasion by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In some embodiments of any of the above aspects, the cancer cell invasion or metastasis occurs along a nerve.

In another aspect, the invention provides a method of increasing cancer cell death by contacting the cancer cell with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of increasing cancer cell death by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of preventing tumor initiation by contacting a tumor or a tissue at risk of developing a tumor with an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of preventing tumor initiation by administering an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In some embodiments of any of the above aspects, the cancer or tumor is a neuro-dependent cancer or tumor.

In some embodiments of any of the above aspects, the method includes administering to a subject that has or is at risk of developing a cancer listed in column 2 of Table 10 an effective amount of a neuromodulating agent that modulates a corresponding gene listed in column 1 of Table 10.

In another aspect, the invention provides a method of decreasing the growth or volume of a neuro-dependent cancer by contacting the tumor with an effective amount of an agent selected from a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of decreasing the growth or volume of a neuro-dependent cancer by administering an effective amount of an agent selected from a

neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject with neuro-dependent cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject identified as having neuro-dependent cancer by administering to the subject an effective amount of a neuromodulating agent selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In some embodiments of any of the above aspects, the neuro-dependent cancer overexpresses one or more neurome genes. In some embodiments, the neuromodulating agent reduces the expression of the one or more overexpressed genes or the activity of the protein encoded by the one or more overexpressed genes.

In some embodiments of any of the above aspects, the neuro-dependent cancer under- expresses one or more neurome genes. In some embodiments, the neuromodulating agent increases the expression the one or more under-expressed genes or the activity of the protein encoded by the one or more under-expressed genes.

In some embodiments of any of the above aspects, the one or more neurome genes is a neurome gene listed in Table 7.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Table 12 by administering to the subject an effective amount of a neuromodulating agent that decreases the expression of a corresponding neurome gene in Table 12 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Table 12 by administering to the subject an effective amount of a neuromodulating agent that decreases the expression of a corresponding neurome gene in Table 12 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Table 12 by contacting the tumor or cancer cell with an effective amount of a

neuromodulating agent that decreases the expression of a corresponding neurome gene in Table 12 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Table 12 by contacting the tumor or cancer cell with an effective amount of a neuromodulating agent that decreases the expression of a corresponding neurome gene in Table 12 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Table 13 by administering to the subject an effective amount of a neuromodulating agent that increases the expression of a corresponding neurome gene in Table 13 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Table 13 by administering to the subject an effective amount of a neuromodulating agent that increases the expression of a corresponding neurome gene in Table 13 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Table 13 by contacting the tumor or cancer cell with an effective amount of a

neuromodulating agent that increases the expression of a corresponding neurome gene in Table 13 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Table 13 by contacting the tumor or cancer cell with an effective amount of a neuromodulating agent that increases the expression of a corresponding neurome gene in Table 13 or the activity of the protein encoded by said neurome gene.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Tables 14A-14C by administering to the subject an effective amount of a neuromodulating agent that modulates the corresponding biosynthetic enzyme or receptor expressed in the neuro- dependent cancer listed in Tables 14A-14C. In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Tables 14A-14C by administering to the subject an effective amount of a neuromodulating agent that modulates the corresponding biosynthetic enzyme or receptor expressed in the neuro-dependent cancer listed in Tables 14A-14C.

In another aspect, the invention provides a method of treating a subject with a neuro-dependent cancer in listed Tables 14A-14C by contacting the tumor or cancer cell with an effective amount of a neuromodulating agent that modulates the corresponding biosynthetic enzyme or receptor expressed in the neuro-dependent cancer listed in Tables 14A-14C.

In another aspect, the invention provides a method of treating a subject identified as having a neuro-dependent cancer in listed Tables 14A-14C by contacting the tumor or cancer cell with an effective amount of a neuromodulating agent that modulates the corresponding biosynthetic enzyme or receptor expressed in the neuro-dependent cancer listed in Tables 14A-14C.

In some embodiments of any of the above aspects, the method further includes profiling the cancer cell or tumor for expression of one or more neurome genes in Table 7 before administering the neuromodulating agent.

In one aspect, the invention provides a method of identifying a subject as having neuro- dependent cancer by profiling a tumor sample from the subject for expression of one or more neurome genes in Table 7.

In some embodiments of any of the above aspects, the neuromodulating agent is selected based on the cancer cell or tumor expression profile of one or more neurome genes in Table 7.

In some embodiments of any of the above aspects, the neuromodulating agent increases the expression of one or more neurome genes in Table 7 or the activity of the protein encoded by said one or more neurome genes.

In some embodiments of any of the above aspects, the neuromodulating agent decreases the expression of one or more neurome genes in Table 7 or the activity of the protein encoded by said one or more neurome genes.

In another aspect, the invention provides a method of treating a subject with cancer, the method including: a) profiling a tumor sample from the subject for expression of one or more neurome genes in Table 7; b) selecting a neuromodulating agent to administer to the subject based on the neurome gene expression profile of the tumor sample; and c) administering an effective amount of the neuromodulating agent to the subject, wherein the neuromodulating agent is selected from the group including a neurotransmission modulator, a neuropeptide signaling modulator, a neuronal growth factor modulator, and a neurome gene expression modulator.

In another aspect, the invention provides a method of treating a subject with small cell lung cancer by administering to the subject an effective amount of a muscarinic receptor antagonist.

In another aspect, the invention provides a method of treating a subject identified as having small cell lung cancer that overexpresses CHRM4 by administering to the subject an effective amount of a muscarinic receptor antagonist.

In another aspect, the invention provides a method of treating a subject with small cell lung cancer, the method including: a) profiling a tumor sample from the subject for expression of CHRM4; b) identifying the subject as having a small cell lung cancer that overexpresses CHRM4 if CHRM4 expression is at least 1 .5 fold higher than a housekeeping gene; and c) administering to the subject an effective amount of a muscarinic receptor antagonist.

In some embodiments of any of the above aspects, the muscarinic receptor antagonist is an antagonist listed in Table 2A or 2E. In some embodiments, the muscarinic receptor antagonist is a CHRM4 antagonist selected from the group including AFDX-384, dicycloverine, himbacine, mamba toxin 3, PD-102,807, PD-0298029, and tropicamide.

In some embodiments of any of the above aspects, the cancer is gastrointestinal cancer, gastric cancer, melanoma, pancreatic cancer, urogenital cancer, prostate cancer, gynecological cancer, ovarian cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, CNS cancer, glioma, malignant mesothelioma, non-metastatic or metastatic breast cancer, skin cancer, thyroid cancer, bone or soft tissue sarcoma, paraneoplastic cancer, or a hematologic neoplasia. In some embodiments of any of the above aspects, the cancer is pancreatic cancer. In some embodiments of any of the above aspects, the cancer is glioma. In some embodiments of any of the above aspects, the cancer is SCLC. In some embodiments of any of the above aspects, the cancer is NSCLC. In some embodiments of any of the above aspects, the cancer is breast cancer. In some embodiments of any of the above aspects, the cancer is prostate cancer. In some embodiments of any of the above aspects, the cancer is gastric cancer. In some embodiments of any of the above aspects, the cancer is melanoma.

In some embodiments of any of the above aspects, the neuromodulating agent is a dopamine agonist, adrenergic agonist, nicotinic agonist, muscarinic agonist, serotonin agonist, glutamate receptor agonist, histamine agonist, cannabinoid receptor agonist, purinergic receptor agonist, GABA agonist, neuropeptide Y receptor agonist, somatostatin receptor agonist, CGRP receptor agonist, tachykinin receptor agonist, VIP receptor agonist, opioid agonist, oxytocin receptor agonist, or vasopressin receptor agonist. In some embodiments, the agonist is selected from an agonist listed in Tables 2A-2L.

In some embodiments of any of the above aspects, the neuromodulating agent is a dopamine antagonist, adrenergic antagonist, nicotinic antagonist, muscarinic antagonist, serotonin antagonist, glutamate receptor antagonist, histamine antagonist, cannabinoid receptor antagonist, purinergic receptor antagonist, GABA antagonist, neuropeptide Y receptor antagonist, somatostatin receptor antagonist, CGRP receptor antagonist, tachykinin receptor antagonist, VIP receptor antagonist, opioid antagonist, oxytocin receptor antagonist, or vasopressin receptor antagonist. In some embodiments, the antagonist is selected from an antagonist listed in Tables 2A-2L. In some embodiments, the antagonist is a purinergic receptor antagonist listed in Tables 2A or 2K. In some embodiments, the purinergic receptor antagonist is an adenosine receptor antagonist. In some embodiments, the adenosine receptor antagonist is MRS-1220 or KW3902. In some embodiments, the antagonist is a dopamine antagonist listed in Table 2A or 2C. In some embodiments, the dopamine antagonist is haloperidol or L-741 ,626. In some embodiments, the cancer or tumor expresses a dopamine receptor. In some embodiments, the antagonist is a histamine antagonist listed in Table 2A or 2I. In some embodiments, the histamine antagonist is acrivastine, azelastine, astemizole, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, or cetirizine.

In some embodiments of any of the above aspects, the neuromodulating agent is neuropeptide Y,

CGRP, somatostatin, bombesin, cholecystokinin, dynorphin, enkephalin, endorphin, gastrin glucagon, melatonin, motilin, neurokinin A, neurokinin B, orexin, oxytocin, pancreatic peptide, peptide YY, substance P, or vasoactive intestinal peptide.

In some embodiments of any of the above aspects, the neuromodulating agent is a neuropeptide Y, CGRP, somatostatin, bombesin, cholecystokinin, dynorphin, enkephalin, endorphin, gastrin glucagon, melatonin, motilin, neurokinin A, neurokinin B, orexin, oxytocin, pancreatic peptide, peptide YY, substance P, or vasoactive intestinal peptide blocking antibody.

In some embodiments of any of the above aspects, the neuromodulating agent is a blocking or neutralizing antibody against BDNF, NGF, LIF, GDNF, sortilin, artemin, neurturin, CNTF, IGF, TGFpl , TGFp2, TGFp3, NTF3, NTF4, persephin, or VEGFA. In some embodiments, the neuromodulating agent is a human anti-NGF antibody.

In some embodiments of any of the above aspects, the neuromodulating agent is a

neurotransmission modulator. In some embodiments, the neurotransmission modulator is a

neurotransmitter listed in Tables 1 A-1 B a neurotransmitter encoded by a gene in Table 7, an agonist or an antagonist of a neurotransmitter of neurotransmitter receptor listed in Tables 1 A-1 B or encoded by a gene in Table 7, a neurotransmission modulator listed in Table 2M, a modulator of a biosynthesis, channel, ligand receptor, signaling, structural, synaptic, vesicular, or transporter protein encoded by a gene in Table 7, a channel or transporter protein encoded by a gene in Table 8, or a neurotoxin listed in Table 3. In some embodiments, the neurotransmission modulator is a neurotoxin listed in Table 3. In some embodiments, the neurotoxin is tetanospasmin or botulinum toxin. In some embodiments, the agonist or antagonist is an agonist or antagonist listed in Tables 2A-2K.

In some embodiments of any of the above aspects, the neuromodulating agent is a neuropeptide signaling modulator. In some embodiments, the neuropeptide signaling modulator is a neuropeptide listed in Tables 1 A-1 B or encoded by a gene in Table 7 or analog thereof, an agonist or antagonist of a neuropeptide or neuropeptide receptor listed in in Tables 1 A-1 B or encoded by a gene in Table 7, or a modulator of a biosynthesis, ligand, receptor, or signaling protein encoded by a gene in Table 7. In some embodiments, the neuropeptide has at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity to the neuropeptide sequence referenced by accession number or Entrez Gene ID in Table 1 A-1 B or Table 7. In some embodiments, the agonist or antagonist is an agonist or antagonist listed in Table 2A or 2L.

In some embodiments of any of the above aspects, the neuromodulating agent is a neuronal growth factor modulator. In some embodiments, the neuronal growth factor modulator is a neuronal growth factor listed in Table 1 C or encoded by a gene in Table 7 or an analog thereof, or a modulator of a ligand, receptor, structural, synaptic, or signaling protein encoded by a gene in Table 7. In some embodiments, the neuronal growth factor has at least 70%, 75%, 80%, 85%, 90%, 90%, 98%, or 99% identity to the neuronal growth factor sequence referenced by accession number or Entrez Gene ID in Table 1 C or Table 7. In some embodiments, the neuronal growth factor modulator is an antibody listed in Table 5. In some embodiments, the neuronal growth factor modulator is an agonist or antagonist listed in Table 6. In some embodiments, the neuronal growth factor modulator is etanercept, thalidomide, lenalidomide, pomalidomide, pentoxifylline, bupropion, DOI, disitertide, or trabedersen.

In some embodiments of any of the above aspects, the neuromodulating agent is a neurome gene expression modulator. In some embodiments, the neurome gene expression modulator increases or decreases the expression of a neurome gene in Table 7. In some embodiments of any of the above aspects, the neuromodulating agent modulates the expression of a neurome gene in Table 7 or the activity of a protein encoded by a neurome gene in Table 7.

In some embodiments of any of the above aspects, the neuromodulating agent is selected from the group including a neurotransmitter, a neuropeptide, an antibody, a small molecule, a DNA molecule, a RNA molecule, a gRNA, and a viral vector. In some embodiments, the antibody is a blocking antibody. In some embodiments, the RNA molecule is an mRNA or an inhibitory RNA. In some embodiments, the viral vector is selected from the group including an adeno-associated virus (AAV), an adenovirus, a parvovirus, a coronavirus, a rhabdovirus, a paramyxovirus, a picornavirus, an alphavirus, a herpes virus, a poxvirus, and a lentivirus. In some embodiments, the herpes virus is a replication deficient herpes virus.

In some embodiments of any of the above aspects, the neuromodulating agent does not cross the blood brain barrier. In some embodiments, the neuromodulating agent has been modified to prevent blood brain barrier crossing by conjugation to a targeting moiety, formulation in a particulate delivery system, addition of a molecular adduct, or through modulation of its size, polarity, flexibility, or lipophilicity.

In some embodiments of any of the above aspects, the neuromodulating agent does not have a direct effect on the central nervous system or gut.

In some embodiments of any of the above aspects, the neuromodulating agent is administered locally. In some embodiments, the neuromodulating agent is administered intratumorally.

In some embodiments of any of the above aspects, the method further includes administering a second therapeutic agent. In some embodiments, the second therapeutic agent is a checkpoint inhibitor, a chemotherapeutic agent, a biologic cancer agent, an anti-angiogenic drug, a drug that targets cancer metabolism, an antibody that marks a cancer cell surface for destruction, an antibody-drug conjugate, a cell therapy, a commonly used anti-neoplastic agent, or a non-drug therapy. In some embodiments, the checkpoint inhibitor is an inhibitory antibody, a fusion protein, an agent that interacts with a checkpoint protein, an agent that interacts with the ligand of a checkpoint protein, an inhibitor of CTLA-4, an inhibitor of PD-1 , an inhibitor of PDL1 , an inhibitor of PDL2, or an inhibitor of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD1 60, CGEN-1 5049, CHK 1 , CHK2, A2aR, or B-7 family ligands. In some embodiments, the biologic cancer agent is an antibody listed in Table 9.

In some embodiments of any of the above aspects, the neuromodulating agent decreases tumor volume, tumor growth, tumor innervation, cancer cell proliferation, cancer cell invasion, or cancer cell metastasis, or increases cancer cell death.

In some embodiments of any of the above aspects, the method further includes measuring one or more of tumor volume, tumor growth, tumor innervation, cancer cell proliferation, cancer cell invasion, cancer cell metastasis, or tumor neurome gene expression before administration of the neuromodulating agent.

In some embodiments of any of the above aspects, the method further includes measuring one or more of tumor volume, tumor growth, tumor innervation, cancer cell proliferation, cancer cell invasion, cancer cell metastasis, or tumor neurome gene expression after administration of the neuromodulating agent. In some embodiments of any of the above aspects, the method further includes measuring the expression of one or more neurome genes in Table 7 after administration of the neuromodulating agent.

In some embodiments of any of the above aspects, the one or more neurome genes in Table 7 is a channel, transporter, neurotransmitter, neuropeptide, neurotrophic, signaling, synaptic, structural, ligand, receptor, biosynthesis, other, or vesicular gene.

In some embodiments of any of the above aspects, the subject is not diagnosed as having a neuropsychiatric disorder.

In some embodiments of any of the above aspects, the subject is not diagnosed as having high blood pressure or a cardiac condition.

In some embodiments of any of the above aspects, the neuromodulating agent is administered in an amount sufficient to increase or decrease tumor innervation, decrease nerve activity in a tumor, treat the cancer or tumor, cause remission, reduce tumor growth, reduce tumor volume, reduce tumor metastasis, reduce tumor invasion, reduce tumor proliferation, reduce tumor number, increase cancer cell death, increase time to recurrence, or improve survival.

Definitions

As used herein, "administration" refers to providing or giving a subject a therapeutic agent (e.g., a neuromodulating agent), by any effective route. Exemplary routes of administration are described herein below.

As used herein, the term "agonist" refers to an agent (e.g., a neurotransmitter, neuropeptide, small molecule, or antibody) that increases receptor activity. An agonist may activate a receptor by directly binding to the receptor, by acting as a cofactor, by modulating receptor conformation (e.g., maintaining a receptor in an open or active state). An agonist may increase receptor activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. An agonist may induce maximal receptor activation or partial activation depending on the concentration of the agonist and its mechanism of action.

As used herein, the term "analog" refers to a protein of similar nucleotide or amino acid composition or sequence to any of the proteins or peptides of the invention, allowing for variations that do not have an adverse effect on the ability of the protein or peptide to carry out its normal function (e.g., bind to a receptor or initiate neurotransmitter or neuropeptide signaling). Analogs may be the same length, shorter, or longer than their corresponding protein or polypeptide. Analogs may have about 60% (e.g., about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, about 86%, about 88%, about 90%, about 92%, about 94%, about 96%, about 98%, or about 99%) identity to the amino acid sequence of the naturally occurring protein or peptide. An analog can be a naturally occurring protein or polypeptide sequence that is modified by deletion, addition, mutation, or substitution of one or more amino acid residues.

As used herein, the term "antagonist" refers to an agent (e.g., a neurotransmitter, neuropeptide, small molecule, or antibody) that reduces or inhibits receptor activity. An antagonist may reduce receptor activity by directly binding to the receptor, by blocking the receptor binding site, by modulating receptor conformation (e.g., maintaining a receptor in a closed or inactive state). An antagonist may reduce receptor activity by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. An antagonist may also completely block or inhibit receptor activity. Antagonist activity may be

concentration-dependent or -independent.

As used herein, the term "antibody" comprises at least the variable domain of a heavy chain, and normally comprises at least the variable domains of a heavy chain and of a light chain of an

immunoglobulin, which bind to an antigen of interest. Antibodies and antigen-binding fragments, variants, or derivatives thereof include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies. Antibody molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass of immunoglobulin molecule.

As used herein, the term "cancer" refers to a condition characterized by unregulated or abnormal cell growth. The terms "cancer cell," "tumor cell," and "tumor" refer to an abnormal cell, mass or population of cells that result from excessive division that may be malignant or benign and all precancerous and cancerous cells and tissues.

As used herein, the term "cardiac condition" refers to a medical condition directly affecting the heart or circulatory system. Cardiac conditions include abdominal aortic aneurysm, arrhythmia (e.g., supraventricular tachycardia, inappropriate sinus tachycardia, atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation), angina, atherosclerosis, brugada syndrome, cardiac arrest, cardiomyopathy, cardiovascular disease, congenital heart disease, coronary heart disease,

catecholaminergic polymorphic ventricular tachycardia (CVPT), familial hypercholesterolaemia, heart attack, heart failure, heart block, heart valve disease (e.g., heart murmur, valve stenosis, mitral valve prolapse, and heart valve regurgitation), inherited heart conditions, long QT syndrome, progressive cardiac conduction deficit (PCCD), pericarditis, venous thromboembolism, peripheral artery disease, and stroke.

As used herein, the term "cell type" refers to a group of cells sharing a phenotype that is statistically separable based on gene expression data. For instance, cells of a common cell type may share similar structural and/or functional characteristics, such as similar gene activation patterns and antigen presentation profiles. Cells of a common cell type may include those that are isolated from a common tissue (e.g., epithelial tissue, neural tissue, connective tissue, or muscle tissue) and/or those that are isolated from a common organ, tissue system, blood vessel, or other structure and/or region in an organism.

As used herein, a "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In other embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.

As used herein, an agent that "does not cross the blood brain barrier" is an agent that does not significantly cross the barrier between the peripheral circulation and the brain and spinal cord. This can also be referred to as "blood brain barrier impermeable" agent. Agents will have a limited ability to cross the blood brain barrier if they are not lipid soluble or have a molecular weight of over 600 Daltons. Agents that typically cross the blood brain barrier can be modified to become blood brain barrier impermeable based on chemical modifications that increase the size or alter the hydrophobicity of the agent, packaging modifications that reduce diffusion (e.g., packaging an agent within a microparticle or nanoparticle), and conjugation to biologies that direct the agent away from the blood brain barrier (e.g., conjugation to a pancreas-specific antibody). An agent that does not cross the blood brain barrier is an agent for which 30% or less (e.g., 30%, 25%, 20%, 15%, 10%, 5%, 2% or less) of the administered agent crosses the blood brain barrier.

As used herein, an agent that "does not have a direct effect on the central nervous system (CNS) or gut" is an agent that does not directly alter neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut when administered according to the methods described herein. This may be assessed by administering the agents to animal models and performing electrophysiological recordings or immunohistochemical analysis. An agent will be considered not to have a direct effect on the CNS or gut if administration according to the methods described herein has an effect on

neurotransmission, neuronal numbers, or neuronal morphology in the CNS or gut that is 50% or less (e.g., 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or less) of the effect observed if the same agent is administered directly to the CNS or gut.

As used herein, the terms "effective amount," "therapeutically effective amount," and a "sufficient amount" of composition, vector construct, viral vector or cell described herein refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount" or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating cancer it is an amount of the composition, vector construct, viral vector or cell sufficient to achieve a treatment response as compared to the response obtained without administration of the composition, vector construct, viral vector or cell. The amount of a given composition described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. Also, as used herein, a "therapeutically effective amount" of a composition, vector construct, viral vector or cell of the present disclosure is an amount which results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of a composition, vector construct, viral vector or cell of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regime may be adjusted to provide the optimum therapeutic response.

As used herein, the term "high blood pressure" refers to a chronic medical condition in which the systemic arterial blood pressure is elevated. It is classified as blood pressure above 140/90 mmHg.

As used herein, the terms "increasing" and "decreasing" refer to modulating resulting in, respectively, greater or lesser amounts, of function, expression, or activity of a metric relative to a reference. For example, subsequent to administration of an neuromodulating agent in a method described herein, the amount of a marker of a metric (e.g., T cell polarization) as described herein may be increased or decreased in a subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% or more relative to the amount of the marker prior to administration. Generally, the metric is measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least one week, one month, 3 months, or 6 months, after a treatment regimen has begun.

As used herein, the term "innervated" refers to a tissue (e.g., a tumor) that contains nerves. "Innervation" refers to the process of nerves entering a tissue.

As used herein, "locally" or "local administration" means administration at a particular site of the body intended for a local effect and not a systemic effect. Examples of local administration are epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect.

As used herein, the terms "neuro-dependent cancer" and "neuro-dependent tumor" refer to cancer or tumor cells that are characterized in that they express one or more neurome genes, e.g., the genes listed in Tables 1 A-1 C, Table 7, and Table 8. Neuro-dependent cancers or tumors are responsive to neuromodulating agents as described herein. Cancer or tumor cells can be identified as neuro- dependent using standard techniques known in the art (e.g., quantitative PCR, RNA sequencing, and immunohistochemistry on cancer or tumor cell samples). Neuro-dependent cancers can overexpress or under-express neurome genes, and neuro-dependent cancers that express neuronal growth factors can promote tumor innervation. Some neuro-dependent cancers express both neurotransmitter or neuropeptide-related genes and genes for the corresponding receptors, making them capable of autocrine signaling. Patients with neuro-dependent cancers can be treated using the compositions and methods described herein to target the one or more neurome genes expressed by the cancer, and can be treated with a neuromodulating agent alone or in combination with existing anti-cancer therapies.

As used herein, a "neuromodulating agent" is an agent that affects a nerve impulse, a nerve function, one or more components of a neural pathway, neural structure, function, or activity in a neuron or a cell of an innervated tissue, e.g., in the peripheral nervous system. A neuromodulating agent may, e.g., increase or decrease neurogenesis; potentiate or inhibit the transmission of a nerve impulse;

increase or decrease innervation of a tissue or tumor; or increase or decrease adrenergic, dopaminergic, cholinergic, serotonergic, glutamatergic, purinergic, GABAergic, or neuropetidergic signaling in a nerve or cell of an innervated tissue. A neuromodulating agent may be a neuropeptide, a neurotoxin, or a neurotransmitter, and may be any type of agent such as a small molecule (e.g. a neuropeptide or neurotransmitter agonist or antagonist), a peptide, a protein (e.g., an antibody or receptor fusion protein) or a nucleic acid (e.g., a therapeutic mRNA). Neuromodulating agents include neurotransmission modulators, neuropeptide signaling modulators, neuronal growth factor modulators, and neurome gene expression modulators.

As used herein, the term "neurome gene" refers to a gene expressed by a cell or tissue of the nervous system. A list of exemplary neurome genes is provided in Tables 1 A-1 C, Table 7, and Table 8. Non-nervous system cells and tissues (e.g., tumors) can also express neurome genes, and the invention includes methods of profiling non-nervous system cells and tissues for neurome gene expression, modulating neurome gene expression in in non-nervous system cells and tissues, and treating cancer based on neurome gene expression in in non-nervous system cells and tissues.

As used herein, the term "neurome gene expression modulator" refers to a neuromodulating agent that affects gene expression (e.g., gene transcription, gene translation, or protein levels) of one or more neurome genes. A neurome gene expression modulator may increase or decrease gene expression by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or more. Neurome gene expression modulators may increase gene expression through epigenetic modifications (e.g., demethylation or acetylation), post-translational modifications (e.g., reducing ubiquitination, or altering sumoylation or phosphorylation), by increasing mRNA translation and stability, or through delivery of exogenous genetic material (e.g., a viral vector expressing a gene of interest). Neurome gene expression modulators may decrease gene expression through epigenetic modifications (e.g., methylation or deacetylation), post-translational modifications (e.g., increasing ubiquitination, or altering sumoylation or phosphorylation), or by decreasing mRNA translation and stability (e.g., using miRNA, siRNA, shRNA, or other therapeutic RNAs).

As used herein, the term "neuronal growth factor modulator" refers to a neuromodulating agent that regulates neuronal growth, development, or survival. Neuronal growth factors include proteins that promote neurogenesis, neuronal growth, and neuronal differentiation (e.g., neurotrophic factors NGF, NT3, BDNF, CNTF, and GDNF), proteins that promote neurite outgrowth (e.g., axon or dendrite outgrowth or stabilization), or proteins that promote synapse formation (e.g., synaptogenesis, synapse assembly, synaptic adhesion, synaptic maturation, synaptic refinement, or synaptic stabilization). These processes lead to innervation of tissue, including neural tissue, muscle, and tumors, and the formation of synaptic connections between two or more neurons and between neurons and non-neural cells (e.g., tumor cells). A neuronal growth factor modulator may block one or more of these processes (e.g., through the use of antibodies that block neuronal growth factors or their receptors) or promote one or more of these processes (e.g., through the use of these proteins or analogs or peptide fragments thereof). Exemplary neuronal growth factors are listed in Table 1 C.

As used herein, the term "neuropeptide signaling modulator" refers to a neuromodulating agent that either induces or increases neuropeptide signaling, or decreases or blocks neuropeptide signaling. Neuropeptide signaling modulators can increase or decrease neuropeptide signaling by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neuropeptides and neuropeptide receptors are listed in Tables 1 A-1 B. Neuropeptide signaling modulators that induce or increase neuropeptide signaling include neuropeptides and analogs and fragments thereof, agents that increase neuropeptide receptor activity (e.g., neuropeptide agonists), and agents that reduce neuropeptide degradation or reuptake. Neuropeptide signaling modulators that decrease or block neuropeptide signaling include agents that reduce or inhibit neuropeptide receptor activity (e.g., neuropeptide antagonists), agents that bind to neuropeptides or block their interaction with receptors (e.g.,

neuropeptide blocking antibodies), or agents that increase neuropeptide degradation or clearance.

Exemplary neuropeptide agonists and antagonists are listed in Table 2A and 2L.

As used herein, the term "neuropsychiatry disorder" refers to a psychiatric or mental disorder that may cause suffering or an impaired ability to function. A neuropsychiatric disorder is a syndrome characterized by clinically significant disturbance in an individual's cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning. Neuropsychiatric disorders may be diagnosed by psychiatrists, psychologists, neurologists, or physicians. Neuropsychiatric disorders include mood disorders (e.g., depression, bipolar depression, major depressive disorder), psychotic disorders (e.g., schizophrenia, schizoaffective disorder), personality disorders (e.g., borderline personality disorder, obsessive compulsive personality disorder, narcissistic personality disorder), eating disorders, sleep disorders, sexual disorders, anxiety disorders (e.g., generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder), developmental disorders (e.g., autism, attention deficit disorder, attention deficit hyperactivity disorder), benign forgetfulness, childhood learning disorders, Alzheimer's disease, addiction, and others listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM).

As used herein, the term "neurotransmission modulator" refers to a neuromodulating agent that either induces or increases neurotransmission or decreases or blocks neurotransmission.

Neurotransmission modulators can increase or decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmitters and neurotransmitter receptors are listed in Tables 1 A-1 B. Neurotransmission modulators may increase neurotransmission by increasing neurotransmitter synthesis or release, preventing neurotransmitter reuptake or degradation, increasing neurotransmitter receptor activity, increasing neurotransmitter receptor synthesis or membrane insertion, decreasing neurotransmitter degradation, and regulating neurotransmitter receptor

conformation. Neurotransmission modulators that increase neurotransmission include neurotransmitters and analogs thereof and neurotransmitter receptor agonists. Neurotransmission modulators may decrease neurotransmission by decreasing neurotransmitter synthesis or release, increasing

neurotransmitter reuptake or degradation, decreasing neurotransmitter receptor activity, decreasing neurotransmitter receptor synthesis or membrane insertion, increasing neurotransmitter degradation, regulating neurotransmitter receptor conformation, and disrupting the pre- or postsynaptic machinery. Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release.

As used herein, the term "percent (%) sequence identity" refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence that are identical to the amino acid (or nucleic acid) residues of a reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity (e.g., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software, such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, a reference sequence aligned for comparison with a candidate sequence may show that the candidate sequence exhibits from 50% to 100% sequence identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purposes may be, for example, at least 30%, (e.g., 30%, 40, 50%, 60%, 70%, 80%, 90%, or 100%) of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid residue as the corresponding position in the reference sequence, then the molecules are identical at that position.

As used herein, a "pharmaceutical composition" or "pharmaceutical preparation" is a composition or preparation, having pharmacological activity or other direct effect in the mitigation, treatment, or prevention of disease, and/or a finished dosage form or formulation thereof and which is indicated for human use.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.

As used herein, the term "proliferation" refers to an increase in cell numbers through growth and division of cells.

As used herein, the term "sample" refers to a specimen (e.g., blood, blood component (e.g., serum or plasma), urine, saliva, amniotic fluid, cerebrospinal fluid, tissue (e.g., placental or dermal), pancreatic fluid, chorionic villus sample, and cells) isolated from a subject.

As used herein, the terms "subject" and "patient" refer to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

"Treatment" and "treating," as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition ; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. "Ameliorating" or "palliating" a disease or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 A-1 C are a series of graphs showing that adenosine receptor antagonists inhibit cancer cell growth. Adenosine receptor antagonists were applied to cancer cell lines in vitro. Adenosine Receptor 1 (A1 R) antagonist KW3902 inhibited the growth of BXPC3 pancreatic cancer cells and NCI- H82 small cell lung cancer cells in vitro at low micromolar concentrations (Figs. P.1 A-B). Additionally, Adenosine Receptor 3 (A3R) antagonist MRS-1220 inhibited the growth of NCI-H82 small cell lung cancer cells in vitro at low micromolar concentrations (Fig. P.1 C).

FIG. 2 is a graph showing that dopamine antagonist haloperidol decreases tumor weight in mice. Mice with orthotopic MIAPACA2 pancreatic cancer were treated with intraperitoneal (IP) injection of vehicle, haloperidol, chemotherapeutic agent gemcitabine, or a combination of haloperidol and gemcitabine. Mice that received Haldol saw a -50% reduction in tumor weight at the end of study (1 50 mg vs 300 mg for the vehicle treatment group). This reduction was equivalent to the reduction observed in the gemcitabine treatment group. The combination treatment group showed a reduction of tumor weight by about 67% compared to the vehicle treatment control group (200 mg vs 300 mg).

FIG. 3 is a series of images showing that dopamine antagonist L-741 ,626 induces cancer cell killing in a mouse xenograft model. Small cell lung cancer cell tumors in mice treated with dopamine antagonist in microcassette. Microdose drug delivery devices containing dopamine (DRD2) antagonist L- 741 ,626 or chemotherapeutic agent cisplatin were implanted into patient-derived xenograft tumors in mice. Patient-derived xenograft tumors from patient 5197 showed a dose-dependent cell killing in response to L-741 ,626, as measured by CC3 positive tissue (left). The same sample showed a negative gradient for phospho-AKT indicating that L-741 ,626 inhibited dopamine receptor signaling (second from left). The same tumor showed minimal cell killing in response to cisplatin, suggesting that dopamine antagonism is killing the cells through an independent mechanism (second from right). Patient-derived xenograft tumors from patient 5217 that expressed ~10x lower levels of DRD2 mRNA compared to patient 5197 were at all not impacted by treatment with the L-741 ,626 dopaminergic antagonist, suggesting that the effect is mediated through dopamine receptor signaling (right).

FIGS. 4A-4B is a series of histograms showing that dopamine antagonists inhibit the growth of cultured glioma cells. DRD2 antagonists haloperidol (FIG. 4A) and L741 ,626 (FIG. 4B) were added to wells containing glioma cell lines A172, LN-1 8, T98G, LN 299, U87, and U1 18 at a range of

concentrations between 1 μΜ and 20 μΜ. Cell growth was assessed after 9 days in culture. Haloperidol and L741 ,626 were able to reduce the number of glioblastoma cells growing in culture compared to DMSO control in a dose-dependent fashion in the cell lines (FIGS. 4A-4B). The effect was strongest for both agents in A172, LN-1 8, LN 229, and U1 18 cell lines.

FIG. 5 is a heatmap of a tumor neurome gene signature. 1 152 primary tumors (columns) were classified by their RNA expression of 60 different neurotransmitter receptors (rows). The tissue of origin for each tumor is denoted by the colored identifier bar at the top of each column. These data show that the neurological gene signature of a tumor did not always correspond with the tissue type of origin.

FIG. 6 is a plot of a principal components analysis of the neurome gene signature data.

Neurotransmitter receptor gene expression enabled tumors to be clustered into five distinct taxa, represented by different shapes in the graph.

FIG. 7 is a series of bar charts showing that tissue of origin does not correlate to neurological taxonomy. Representation from most of all of the taxa is observed for each tumor type. These data demonstrate that the neurological taxonomy does not correspond to the tissue of origin and thus represents a new taxonomy for classifying tumors.

FIGS. 8A-8F are a series of graphs showing the classification of lung cancers based on neurome gene expression. 276 lung cancers were analyzed using RNA sequencing. Distinct clusters of tumor types were identified based on their (1 ) co-expression of muscarinic receptor CHRM4 and dopamine receptor DRD2, (2) expression of adrenergic receptor ADRB2, or (3) low expression of all three.

Neurome gene expression clustering does not correspond to common histological taxonomy, some small cell lung cancer (SCLC) samples appear to be CHRM4 and DRD2 high (Group 1 , FIG. 8D), while others are negative (Group 3), and non-small cell lung cancers (NSCLC) samples are distributed into all three groups (FIGS. 8A-8C).

FIGS. 9A-9B are a pair of graphs showing 5 year survival in patients with low or high expression of Chrna6 in intratumoral T regulatory cells (Tregs). Analysis of gene expression of tumor infiltrating Tregs in was performed in 275 non-small cell lung cancer (NSCLC) patients (FIG. 9A) and 177 colorectal cancer (CRC) patients (FIG. 9B) and normalized to CD3G in order to account for differential immune infiltration. Data analysis revealed that patients with low intratumoral Treg expression of Chrna6 had a significantly better 5 year survival than patients with high intratumoral Treg expression of Chrna6. The relationship between Chrna6 expression and survival was observed in both NSCLC and CRC. DETAILED DESCRIPTION

Neuromodulating agents described herein can surprisingly have effects on cancer cells, such as effects on cancer cell proliferation, cancer cell death, tumor growth, tumor initiation, tumor innervation, cancer cell metastasis, and cancer cell invasion. It has been found that neuromodulating agents thus can have a therapeutic effect on cancer. I. Neuromodulating Agents

Neuromodulating agents described herein can agonize or inhibit genes or proteins in neuromodulatory signaling pathways, in order to treat cancer. Neuromodulatory signaling pathway genes are listed in Tables 1 A-C (column 1 ). Additional neurome genes (e.g., genes expressed by a nervous system cell or tissue) are listed in Table 7 and Table 8. The level, activity and/or function of such genes and the proteins they encode can be modulated by pharmaceutical compositions comprising agents described herein. Neuromodulating agents also include neurotransmitter and neuropeptide ligands listed in Table 1 B and neuronal growth factors listed in Table 1 C.

Neuromodulating agents can be divided into four major categories: 1 ) neurotransmission modulators (e.g., agents that increase or decrease neurotransmission, such as neurotransmitter agonists or antagonists or neurotoxins), 2) neuropeptide signaling modulators (e.g., neuropeptides and neuropeptide agonists or antagonists), 3) neuronal growth factor modulators (e.g., neuronal growth factors or agents that agonize or antagonize neuronal growth factor signaling), and 4) neurome gene expression modulators (e.g., agents that modulate expression of a gene listed in Table 7 or Table 8). These classes of neuromodulating are described in more detail herein below.

TABLE 1 A: NEUROTRANSMITTER & NEUROPEPTIDE GENES & PATHWAYS

Gene Pathway Type Accession Entrez

Number Gene ID

Adrbl Adrenergic/ Receptor P08588 153

Neurotransmitter

Adrb2 Adrenergic/ Receptor P07550 154

Neurotransmitter

Adrb3 Adrenergic/ Receptor P13945 155

Neurotransmitter

Adrbkl Adrenergic Kinase P25098 156

Adrbk2 Adrenergic Kinase P35626 157

AGRN Neuropeptide Ligand 000468 375790

AGRP Neuropeptide Ligand 000253 181

AGT Neuropeptide Ligand P01019 183

AGTR1 Neuropeptide Receptor P30556 185

APLN Neuropeptide Ligand Q9ULZ1 8862

ASIP Neuropeptide Ligand P42127 434

AVP Neuropeptide Ligand P01 185 551

AVPR1 A Neuropeptide Receptor P30560 552

AVPR1 B Neuropeptide Receptor P47901 553

AVPR2 Neuropeptide Receptor P30518 554

BACE1 Neurotransmitter Biosynthesis P56817 23621

BCHE Neurotransmitter Biosynthesis P06276 590

BDKRB2 Neuropeptide Receptor P3041 1 624

BRS3 Neuromodulator Receptor P32247 P32247

C1 QBP Neuropeptide Receptor Q07021 708

C4orf48 Neuropeptide Ligand Q5BLP8 401 1 15

C6orf89 Neuromodulator Receptor Q6UWU4 221477

CALCA Neuropeptide Ligand P06881 796

CALCB Neuropeptide Ligand P10092 797

CALCR Neuropeptide Receptor P30988 799

CALCRL Neuropeptide Receptor Q16602 10203

CARTPT Neuropeptide Ligand Q16568 9607

CASR Neuropeptide Biosynthesis P41 180 846

CCK Neuropeptide Ligand P06307 885

CCKAR Neuropeptide Receptor P32238 886

CCKBR Neuropeptide Receptor P32239 887

CCL2 Neuropeptide Ligand P13500 6347

CHAT Neurotransmitter Biosynthesis P28329 1 103

CHGA Neuropeptide Ligand P10645 1 1 13

CHGB Neuropeptide Ligand P05060 1 1 14 Gene Pathway Type Accession Entrez

Number Gene ID

CHRFAM7A Neurotransmitter Receptor Q494W8 89832

Chrml Cholinergic/ Receptor P1 1229 1 128

Neurotransmitter

Chrm2 Cholinergic/ Receptor P08172 1 129

Neurotransmitter

Chrm3 Cholinergic/ Receptor P20309 1 131

Neurotransmitter

Chrm4 Cholinergic/ Receptor P08173 1 132

Neurotransmitter

Chrm5 Cholinergic/ Receptor P08912 1 133

Neurotransmitter

Chrnal Cholinergic/ Receptor P02708 1 134

Neurotransmitter

Chrnal O Cholinergic/ Receptor Q9GZZ6 57053

Neurotransmitter

Chrna2 Cholinergic/ Receptor Q15822 1 135

Neurotransmitter

Chrna3 Cholinergic/ Receptor P32297 1 136

Neurotransmitter

Chrna4 Cholinergic/ Receptor P43681 1 137

Neurotransmitter

Chrna5 Cholinergic/ Receptor P30532 1 138

Neurotransmitter

Chrna6 Cholinergic/ Receptor Q15825 8973

Neurotransmitter

Chrna7 Cholinergic/ Receptor P36544 1 139

Neurotransmitter

Chrna9 Cholinergic/ Receptor Q9UGM1 55584

Neurotransmitter

Chrnbl Cholinergic/ Receptor P1 1230 1 140

Neurotransmitter

Chrnb2 Cholinergic/ Receptor P17787 1 141

Neurotransmitter

Chrnb3 Cholinergic/ Receptor Q05901 1 142

Neurotransmitter

Chrnb4 Cholinergic/ Receptor P30926 1 143

Neurotransmitter Gene Pathway Type Accession Entrez

Number Gene ID

Chrnd Cholinergic/ Receptor Q07001 1 144

Neurotransmitter

Chrne Cholinergic/ Receptor Q04844

Neurotransmitter 1 145

Chrng Cholinergic/ Receptor P07510 1 146

Neurotransmitter

CLCF1 Neuropeptide Ligand Q9UBD9 23529

CNR1 Cannabinoid/ Receptor P21554 1268

Neurotransmitter

CNR2 Cannabinoid/ Receptor P34972 1269

Neurotransmitter

CNRIP1 Neurotransmitter Receptor Q96F85 25927

COMT Neurotransmitter Biosynthesis P21964 1312

CORT Neuropeptide Ligand 000230 1325

CPA4 Neurotransmitter Biosynthesis Q9UI42 51200

CPE Neuropeptide/ Biosynthesis P16870 1363

Neurotransmitter

CRCP Neuropeptide Receptor 075575 27297

CREM Neurotransmitter Signaling Q03060 1390

CRH Neuropeptide Ligand Q 13324 1392

CRHBP Neuropeptide Receptor P24387 1393

CRHR1 Neuropeptide Receptor P34998 1394

CRHR2 Neuropeptide Receptor Q 13324 1395

CTSH Neuropeptide Biosynthesis P09668 1512

CTSV Neuropeptide Biosynthesis 06091 1 1515

CYSLTR1 Neuropeptide Receptor Q9Y271 10800

CYSLTR2 Neuropeptide Receptor Q9NS75 57105

DAG LA Neurotransmitter Q9Y4D2

(Cannabinoid) Biosynthesis 747

DAG LB Neurotransmitter Q8NCG7

(Cannabinoid) Biosynthesis 221955

DBH Neurotransmitter Biosynthesis P09172 1621

DBI Neuropeptide Ligand P07108 1622

DDC Neurotransmitter Biosynthesis P2071 1 1644

DGKI Neurotransmitter Biosynthesis 075912 9162

DOPO Dopaminergic Receptor P09172 1621

DPP4 Neurotransmitter Biosynthesis P27487 1803 Gene Pathway Type Accession Entrez

Number Gene ID

Drd1 Dopaminergic/ Receptor P21728 1812

Neurotransmitter

Drd2 Dopaminergic/ Receptor P14416 1813

Neurotransmitter

Drd3 Dopaminergic/ Receptor P35462 1814

Neurotransmitter

Drd4 Dopaminergic/ Receptor P21917 1815

Neurotransmitter

Drd5 Dopaminergic/ Receptor P21918 1816

Neurotransmitter

ECEL1 Neurotransmitter Biosynthesis 095672 9427

EDN1 Neuropeptide Ligand P05305 1906

EDN2 Neuropeptide Ligand P20800 1907

EDN3 Neuropeptide Ligand P14138 1908

EDNRA Neuropeptide Receptor P25101 1909

EDNRB Neuropeptide Receptor P24530 1910

FAAH Neurotransmitter Biosynthesis 000519 2166

FAP Neuropeptide Biosynthesis Q12884 2191

FNTA Neurotransmitter Signaling P49354 2339

F0LH1 Neuropeptide Biosynthesis Q04609 2346

FSHR Neuropeptide Receptor P23945 2492

GABARAP Amine Receptor 095166 1 1337

Neuromodulator/

Neurotransmitter

GABARAPL1 Amine Receptor Q9H0R8 23710

Neuromodulator

GABARAPL2 Amine Receptor P60520 1 1345

Neuromodulator

GABBR1 Amine Receptor Q9UBS5 2550

Neuromodulator/

Neurotransmitter

GABBR2 Amine Receptor 075899 9568

Neuromodulator

GABRA1 Amine Receptor P14867 2554

Neuromodulator/

Neurotransmitter Gene Pathway Type Accession Entrez

Number Gene ID

GABRA2 Amine Receptor P47869 2555

Neuromodulator/

Neurotransmitter

GAB R A3 Neurotransmitter Receptor P34903 2556

GABRA4 Neurotransmitter Receptor P48169 2557

GABRA5 Amine Receptor P31644 2558

Neuromodulator/NT

GABRA6 Neurotransmitter Receptor Q 16445 2559

GABRB1 Neurotransmitter Receptor P18505 2560

GABRB2 Amine Receptor P47870 2561

Neuromodulator/

Neurotransmitter

GABRB3 Amine Receptor P28472 2562

Neuromodulator/

Neurotransmitter

GABRD Amine Receptor 014764 2563

Neuromodulator/

Neurotransmitter

GABRE Neurotransmitter Receptor P78334 2564

GABRG1 Neurotransmitter Receptor Q8N1 C3 2565

GABRG2 Amine Receptor P18507 2566

Neuromodulator/

Neurotransmitter

GABRG3 Neurotransmitter Receptor Q99928 2567

GABRP Neurotransmitter Receptor 000591 2568

GABRQ Neurotransmitter Receptor Q9UN88 55879

GABRR1 Amine Receptor P24046 2569

Neuromodulator/

Neurotransmitter

GABRR2 Amine Receptor P28476 2570

Neuromodulator/

Neurotransmitter

GABRR3 Neurotransmitter Receptor A8MPY1 200959

GAD1 Neurotransmitter Biosynthesis Q99259 2571

GAD2 Neurotransmitter Biosynthesis Q05329 2572

GAL Neuropeptide Ligand P22466 51083

GALP Neuropeptide Ligand Q810H5 85569

GALR1 Neuropeptide Receptor P4721 1 2587 Gene Pathway Type Accession Entrez

Number Gene ID

GALR2 Neuropeptide Receptor 043603 881 1

GALR3 Neuropeptide Receptor 060755 8484

GAST Neuropeptide Ligand P01350 2520

GCGR Secretin Receptor P47871 2642

GCHFR Neurotransmitter Biosynthesis P30047 2644

GH1 Neuropeptide Ligand P01241 2688

GHRH Neuropeptide Ligand P01286 2691

GHRHR Neuropeptide Receptor Q02643 2692

GHRL Neuropeptide Ligand Q9UBU3 51738

GIP Neuropeptide Ligand P09681 2695

GLRA1 Neurotransmitter Receptor P23415 2741

GLRA2 Neurotransmitter Receptor P23416 2742

GLRA3 Neurotransmitter Receptor 07531 1 8001

GLRA4 Neurotransmitter Receptor Q5JXX5 441509

GLRB Neurotransmitter Receptor P48167 2743

GLS Neurotransmitter Biosynthesis 094925 2744

GLS2 Neurotransmitter Biosynthesis Q9UI32 27165

GluA1 (GluR1 ) Amine Receptor P42261 2890

Neuromodulator

GluK1 (GluR5) Amine Receptor P39086 2897

Neuromodulator

GLUL Neurotransmitter Biosynthesis P15104 2752

GluN1 (NR1 ) Amine Receptor Q05586 2902

Neuromodulator

GNMT Neurotransmitter Biosynthesis Q 14749 27232

GNRH1 Neuropeptide Ligand P01 148 2796

GNRH2 Neuropeptide Ligand 043555 2797

GPHN Neuropeptide Ligand Q9NQX3 10243

GPER1 Neurotransmitter Receptor Q99527 2852

GPR1 Neurotransmitter Receptor P46091 2825

GPR139 Neurotransmitter Receptor Q6DWJ6 124274

GPR143 Neurotransmitter Receptor P51810 4935

GPR149 Neurotransmitter Receptor Q86SP6 344758

GPR18 Neurotransmitter Receptor Q 14330 2841

GPR21 Neurotransmitter Receptor Q99679 2844

GPR26 Neurotransmitter Receptor Q8NDV2 2849

GPR3 Neurotransmitter Receptor P46089 2827

GPR35 Neurotransmitter Receptor Q9HC97 2859 Gene Pathway Type Accession Entrez

Number Gene ID

GPR52 Neurotransmitter Receptor Q9Y2T5 9293

GPR55 Neurotransmitter Receptor Q9Y2T6 9290

GPR78 Neurotransmitter Receptor Q96P69 27201

GPR83 Neurotransmitter Receptor Q9NYM4 10888

GPR84 Neurotransmitter Receptor Q9NQS5 53831

GPRASP1 Neurotransmitter Receptor Q5JY77 9737

GPR50 Amine Receptor Q13585 9248

Neuromodulator

GRIA1 Amine Receptor P42261 2890

Neuromodulator/

Neurotransmitter

GRIA2 Amine Receptor P42262 2891

Neuromodulator/

Neurotransmitter

GRIA3 Amine Receptor P42263 2892

Neuromodulator/

Neurotransmitter

GRIA4 Amine Receptor P48058 2893

Neuromodulator/

Neurotransmitter

GRID1 Neurotransmitter Receptor Q9ULK0 2894

GRID2 Neurotransmitter Receptor 043424 2895

GRIK1 Amine Receptor P39086 2897

Neuromodulator/

Neurotransmitter

GRIK2 Amine Receptor Q13002 2898

Neuromodulator/

Neurotransmitter

GRIK3 Amine Receptor Q13003 2899

Neuromodulator/

Neurotransmitter

GRIK4 Amine Receptor Q16099 2900

Neuromodulator/

Neurotransmitter

GRIK5 Amine Receptor Q 16478 2901

Neuromodulator/

Neurotransmitter Gene Pathway Type Accession Entrez

Number Gene ID

GRIN1 Amine Receptor Q05586 2902

Neuromodulator/

Neurotransmitter

GRIN2A Amine Receptor Q12879 2903

Neuromodulator/

Neurotransmitter

GRIN2B Amine Receptor Q 13224 2904

Neuromodulator

GRIN2C Amine Receptor Q14957 2905

Neuromodulator/

Neurotransmitter

GRIN2D Amine Receptor 015399 2906

Neuromodulator/

Neurotransmitter

GRIN3A Amine Receptor Q8TCU5 1 16443

Neuromodulator/

Neurotransmitter

GRIN3B Amine Receptor 060391 1 16444

Neuromodulator/

Neurotransmitter

GRK2 Neurotransmitter Receptor P25098 156

GRK3 Neurotransmitter Receptor P35626 157

GRM1 Neurotransmitter Receptor Q13255 291 1

GRM2 Neurotransmitter Receptor Q14416 2912

GRM3 Neurotransmitter Receptor Q 14832 2913

GRM4 Neurotransmitter Receptor Q 14833 2914

GRM5 Neurotransmitter Receptor P41594 2915

GRM6 Neurotransmitter Receptor 015303 2916

GRM7 Neurotransmitter Receptor Q14831 2917

GRM8 Neurotransmitter Receptor 000222 2918

GRP Neuropeptide Ligand P07492 2922

GRPR Neuropeptide Receptor P30550 2925

HCRT Neuropeptide Ligand 043612 3060

HCRTR1 Neuropeptide/Orexin Receptor 043613 3061

HCRTR2 Neuropeptide/Orexin Receptor 043614 3062

HNMT Neurotransmitter Biosynthesis P50135 3176

HOMER1 Neurotransmitter Receptor Q86YM7 9456 Gene Pathway Type Accession Entrez

Number Gene ID

HRH1 Amine Receptor P35367 3269

Neuromodulator/

Neurotransmitter

HRH2 Amine Receptor P25021 3274

Neuromodulator/

Neurotransmitter

HRH3 Amine Receptor Q9Y5N1 1 1255

Neuromodulator/

Neurotransmitter

HRH4 Amine Receptor Q9H3N8 59340

Neuromodulator/

Neurotransmitter

Htr1 a Serotonin/ Receptor P08908 3350

Neurotransmitter

Htr1 b Serotonin/ Receptor P28222 3351

Neurotransmitter

Htr1 c Serotonin Receptor P28335

Htr1 d Serotonin/ Receptor P28221 3352

Neurotransmitter

Htr1 e Serotonin/ Receptor P28566 3354

Neurotransmitter

Htr1 f Serotonin/ Receptor P30939 3355

Neurotransmitter

Htr2a Serotonin/ Receptor P28223 3356

Neurotransmitter

Htr2b Serotonin/ Receptor P41595 3357

Neurotransmitter

Htr2c Serotonin/ Receptor P28335 3358

Neurotransmitter

Htr3a Serotonin/ Receptor P46098 3359

Neurotransmitter

Htr3b Serotonin/ Receptor 095264 9177

Neurotransmitter

Htr3c Serotonin/ Receptor Q8WXA8 170572

Neurotransmitter

Htr3d Serotonin/ Receptor Q70Z44 200909

Neurotransmitter

HTR3E Neurotransmitter Receptor A5X5Y0 285242 Gene Pathway Type Accession Entrez

Number Gene ID

Htr4 Serotonin/ Receptor Q13639 3360

Neurotransmitter

Htr5a Serotonin/ Receptor P47898 3361

Neurotransmitter

Htr5b Serotonin Receptor P35365 79247

HTR5BP Neurotransmitter Receptor 645694

Htr6 Serotonin/ Receptor P50406 3362

Neurotransmitter

Htr7 Serotonin/ Receptor P32305 3363

Neurotransmitter

IAPP Neuropeptide Ligand P10997 3375

ITPR1 Neurotransmitter Signaling Q 14643 3708

ITPR2 Neurotransmitter Signaling Q14571 3709

ITPR3 Neurotransmitter Signaling Q 14573 3710

KISS1 Neuropeptide Ligand Q15726 3814

KISS1 R Neuropeptide Receptor Q969F8 84634

LEP Neuropeptide Ligand P41 159 3952

LHCGR Neuropeptide Receptor P22888 3973

LIF Neuropeptide Ligand P15018 3976

LTB4R Neuropeptide Receptor Q 15722 1241

LTB4R2 Neuropeptide Receptor Q9NPC1 56413

LYNX1 Neurotransmitter Receptor Q9BZG9 66004

MAOA Neurotransmitter Biosynthesis P21397 4128

MAOB Neurotransmitter Biosynthesis P27338 4129

MC1 R Neuropeptide Receptor Q01726 4157

MC2R Neuropeptide Receptor Q01718 4158

MC3R Neuropeptide Receptor P41968 4159

MC4R Neuropeptide Receptor P32245 4160

MC5R Neuropeptide Receptor P33032 4161

MCHR1 Neuropeptide Receptor Q99705 2847

MCHR2 Neuropeptide Receptor Q969V1 84539

MLN Neuropeptide Ligand P12872 4295

MME Neuropeptide Biosynthesis P08473 431 1

MRAP Neuropeptide Receptor Q8TCY5 56246

MRAP2 Neuropeptide Receptor Q96G30 1 12609

MRGPRF Neurotransmitter Receptor Q96AM1 1 16535

MRGPRX1 Neuropeptide Receptor Q96LB2 259249

MRGPRX2 Neurotransmitter Receptor Q96LB1 1 17194 Gene Pathway Type Accession Entrez

Number Gene ID

MRGPRX3 Neuropeptide Receptor Q96LB0 1 17195

MRGPRX4 Neuropeptide Receptor Q96LA9 1 17196

MTNR1 A Amine Receptor P48039 4543

Neuromodulator/

Neuropeptide

MTNR1 B Amine Receptor P49286 4544

Neuromodulator/

Neuropeptide

NAALAD2 Neuropeptide Biosynthesis Q9Y3Q0 10003

NAMPT NT Biosynthesis P43490 10135

NGF Neuropeptide Ligand P01 138 4803

NISCH Amine Receptor Q9Y2I1 1 1 188

Neuromodulator/

Neurotransmitter

NMB Neuropeptide Ligand P08949 4828

NMBR Neuropeptide Receptor P28336 4829

NMS Neuropeptide Ligand Q5H8A3 129521

NMU Neuropeptide Ligand P48645 10874

NMUR1 Neuropeptide Receptor Q9HB89 10316

NMUR2 Neuropeptide Receptor Q9GZQ4 56923

N0S1 Neurotransmitter Biosynthesis P29475 4842

NPB Neuropeptide Ligand Q8NG41 256933

NPBWR1 Neuropeptide Receptor P48145 2831

NPBWR2 Neuropeptide Receptor P48146 2832

NPFF Neuropeptide Ligand 015130 8620

NPFFR1 Neuropeptide Receptor Q9GZQ6 64106

NPFFR2 Neuropeptide Receptor Q9Y5X5 10886

NPPA Neuropeptide Ligand P01 160 4878

NPPB Neuropeptide Ligand P16860 4879

NPPC Neuropeptide Ligand P23582 4880

NPS Neuropeptide Ligand P0C0P6 594857

NPSR1 Neuropeptide Receptor Q6W5P4 387129

NPTN Neurotransmitter Receptor Q9Y639 27020

NPVF Neuropeptide Ligand Q9HCQ7 641 1 1

NPW Neuropeptide Ligand Q8N729 283869

NPY Neuropeptide Ligand P01303 4852

NPY1 R Neuropeptide Receptor P25929 4886

NPY2R Neuropeptide Receptor P49146 4887 Gene Pathway Type Accession Entrez

Number Gene ID

NPY4R Neuropeptide Receptor P50391 5540

NPY5R Neuropeptide Receptor Q15761 4889

NPY6R Neuropeptide Receptor Q61212 4888

NTS Neuropeptide Ligand Q6FH20 4922

NTSR1 Neuropeptide Receptor P30989 4923

NTSR2 Neuropeptide Receptor Q63384 23620

NXPH1 Neuropeptide Ligand P58417 30010

NXPH2 Neuropeptide Ligand 095156 1 1249

NXPH3 Neuropeptide Ligand 095157 1 1248

NXPH4 Neuropeptide Ligand 095158 1 1247

OGFR Neuropeptide Receptor Q9NZT2 1 1054

OPRD1 Neuropeptide/Opioid Receptor P41 143 4985

OPRK1 Neuropeptide/Opioid Receptor P41 145 4986

OPRL1 Neuropeptide Receptor P41 146 4987

OPRM1 Neuropeptide/Opioid Receptor P35372 4988

OXT Neuropeptide Ligand P01 178 5020

OXTR Neuropeptide Receptor P30559 5021

P2RX1 Neurotransmitter Receptor P51575 5023

P2RX2 Neurotransmitter Receptor Q9UBL9 22953

P2RX3 Neurotransmitter Receptor P56373 5024

P2RX4 Neurotransmitter Receptor Q99571 5025

P2RX5 Neurotransmitter Receptor Q93086 5026

P2RX6 Neurotransmitter Receptor 015547 9127

P2RX7 Neurotransmitter Receptor Q99572 5027

P2RY1 1 Neurotransmitter Receptor Q96G91 5032

PAH Neurotransmitter Biosynthesis P00439 5053

PC Neurotransmitter Biosynthesis P1 1498 5091

PCSK1 Neuropeptide Biosynthesis P29120 5122

PCSK1 N Neuropeptide Ligand/ Q9UHG2 27344

Biosynthesis

PDE1 B Neurotransmitter Signaling Q01064 5153

PDE4A Neurotransmitter Signaling P27815 5141

PDE4D Neurotransmitter Signaling Q08499 5144

PDYN Neuropeptide Ligand P01213 5173

PENK Neuropeptide Ligand P0121 1 5179

PHOX2A Neurotransmitter Biosynthesis 014813 401

PHOX2B Neurotransmitter Biosynthesis Q99453 8929

PIK3CA Neurotransmitter Signaling P42336 5290 Gene Pathway Type Accession Entrez

Number Gene ID

PIK3CB Neurotransmitter Signaling P42338 5291

PIK3CG Neurotransmitter Signaling P48736 5294

PLCB1 Neurotransmitter Signaling Q9NQ66 23236

PLCB2 Neurotransmitter Signaling Q00722 5330

PLCB3 Neurotransmitter Signaling Q01970 5331

PLCB4 Neurotransmitter Signaling Q15147 5332

PLCD1 Neurotransmitter Signaling P51 178 5333

PLCE1 Neurotransmitter Signaling Q9P212 51 196

PLCG1 Neurotransmitter Signaling P19174 5335

PLCL1 Neurotransmitter Signaling Q151 1 1 5334

PLCL2 Neurotransmitter Signaling Q9UPR0 23228

PMCH Neuropeptide Ligand P20382 5367

PNOC Neuropeptide Ligand Q13519 5368

POMC Neuropeptide Ligand P01 189 5443

PPP1 CB Neurotransmitter Signaling P62140 5500

PPP1 CC Neurotransmitter Signaling P36873 5501

PPY Neuropeptide Ligand P01298 5539

PPY2P Neuropeptide Ligand Q9NRI7 23614

PRIMA1 Neurotransmitter Biosynthesis Q86XR5 145270

PRKACG Neurotransmitter Signaling P22612 5568

PRKAR2B Neurotransmitter Signaling P31323 5577

PRKCG Neurotransmitter Signaling P05129 5582

PRKX Neurotransmitter Signaling P51817 5613

PRL Neuropeptide Ligand P01236 5617

PRLH Neuropeptide Ligand P81277 51052

PRLHR Neuropeptide Receptor P49683 2834

PRLR Neuropeptide Receptor P16471 5618

PROK1 Neuropeptide Ligand P58294 84432

PROK2 Neuropeptide Ligand Q9HC23 60675

PROKR1 Neuropeptide Receptor Q8TCW9 10887

PROKR2 Neuropeptide Receptor Q8NFJ6 128674

PTGDR Neuropeptide Receptor Q13258 5729

PTGDR2 Neuropeptide Receptor Q9Y5Y4 1 1251

PTGER1 Neuropeptide Receptor P34995 5731

PTGER2 Neuropeptide Receptor P431 16 5732

PTGER3 Neuropeptide Receptor P431 15 5733

PTGER4 Neuropeptide Receptor P35408 5734

PTGFR Neuropeptide Receptor P43088 5737 Gene Pathway Type Accession Entrez

Number Gene ID

PTGIR Neuropeptide Receptor P431 19 5739

PTGS2 Neuropeptide Biosynthesis P35354 5743

PTH Neuropeptide Ligand P01270 5741

PTH1 R Neuropeptide Receptor Q03431 5745

PTH2 Neuropeptide Ligand Q9Y3E5 1 13091

PTH2R Neuropeptide Receptor P49190 5746

PTHLH Neuropeptide Ligand P12272 5744

PTK2 Neuropeptide Signaling Q05397 5747

PTK2B Neuropeptide Signaling Q14289 2185

PYY Neuropeptide Ligand P10082 5697

PYY2 Neuropeptide Ligand Q9NRI6 23615

PYY3 Neuropeptide Ligand Q5JQD4 644059

QRFP Neuropeptide Ligand P83859 347148

QRFPR Neuropeptide Receptor Q96P65 84109

RAMP1 Neuropeptide Receptor 060894 10267

RAMP2 Neuropeptide Receptor 060895 10266

RAMP3 Neuropeptide Receptor 060896 10268

RIC3 Neurotransmitter Receptor Q7Z5B4 79608

RLN1 Neuropeptide Ligand P04808 6013

RLN2 Neuropeptide Ligand P04090 6019

RLN3 Neuropeptide Ligand Q8WXF3 1 17579

RXFP1 Neuropeptide Receptor Q9HBX9 59350

RXFP2 Neuropeptide Receptor Q8WXD0 122042

RXFP3 Neuropeptide Receptor Q9NSD7 51289

RXFP4 Neuropeptide Receptor Q8TDU9 339403

S1 PR4 Neuropeptide Receptor 095977 8698

SCG2 Neuropeptide Ligand/Vesicles P13521 7857

SCG3 Neuropeptide Ligand/Vesicles Q8WXD2 29106

SCG5 Neuropeptide Ligand/Vesicles P05408 6447

SCT Neuropeptide Ligand P09683 6343

SCTR Secretin Receptor P47872 6344

SHANK3 Neurotransmitter Signaling Q9BYB0 85358

SLC6A1 Amine Transferase P30531 6529

Neuromodulator

SLC6A13 Amine Transferase Q9NSD5 6540

Neuromodulator

Slc6a4 Serotonin Transporter P31645 6532

SNX13 Neurotransmitter Signaling Q9Y5W8 23161 Gene Pathway Type Accession Entrez

Number Gene ID

SPX Neuropeptide Ligand Q9BT56 80763

SST Neuropeptide Ligand P61278 6750

SSTR1 Neuropeptide Receptor P30872 6751

SSTR2 Neuropeptide Receptor P30874 6752

SSTR3 Neuropeptide Receptor P32745 6753

SSTR4 Neuropeptide Receptor P31391 6754

SSTR5 Neuropeptide Receptor P35346 6755

TAAR1 Amine Receptor Q96RJ0 134864

Neuromodulator

TAAR2 Amine Receptor Q9P1 P5 9287

Neuromodulator

TAAR5 Neurotransmitter Receptor 014804 9038

TAC1 Neuropeptide Ligand P20366 6863

TAC3 Neuropeptide Ligand Q9UHF0 6866

TAC4 Neuropeptide Ligand Q86UU9 255061

TACR1 Neuropeptide Receptor P25103 6869

TACR2 Neuropeptide Receptor P21452 6865

TACR3 Neuropeptide Receptor P29371 6870

TBXA2R Neuropeptide Receptor P21731 6915

TH Neurotransmitter Biosynthesis P07101 7054

TPH1 Neurotransmitter Biosynthesis P17752 7166

TPH2 Neurotransmitter Biosynthesis Q8IWU9 121278

TRHDE Neurotransmitter Biosynthesis Q9UKU6 29953

TRH Neuropeptide Ligand P20396 7200

TRHR Neuropeptide Receptor P34981 7201

TSHR Neuropeptide Receptor P16473 7253

UCN Neuropeptide Ligand P55089 7349

UCN2 Neuropeptide Ligand Q96RP3 90226

UCN3 Neuropeptide Ligand Q969E3 1 14131

UTS2 Neuropeptide Ligand 095399 1091 1

UTS2B Neuropeptide Ligand Q756I0 257313

UTS2R Neuropeptide Receptor Q9UKP6 2837

VIP Neuropeptide Ligand P01282 7432

VIPR1 Neuropeptide Receptor P32241 7433

VIPR2 Neuropeptide Receptor P41587 7434 TABLE 1 B: NEUROTRANSMITTERS & NEUROPEPTIDE LIGANDS

Accession

Ligand Pathway Type Number

2-Arachidonoylglycerol Endocannabinoid Ligand

2-Arachidonyl glyceryl ether Endocannabinoid Ligand

3-methoxytyramine Amines Ligand

Acetylcholine Amino Acids Ligand

Adenosine Purine Ligand

Adenosine triphosphate Purine Ligand

Agmatine Amino Acids Ligand

Anandamide Endocannabinoid Ligand

Aspartate Amino Acids Ligand

Bombesin Other Ligand

Carbon monoxide Gas Ligand

Cholecystokinin Gastrins Ligand P06307

Cocaine Other Ligand

Corticotropin Opioids Ligand

D-serine Amino Acids Ligand

Dopamine Monoamines Ligand

Dynorphin Opioids Ligand

Endorphin Opioids Ligand

Enkephaline Opioids Ligand

Epinephrine Monoamines Ligand

Gamma-aminobutyric acid Amino Acids Ligand

Gastrin Gastrins Ligand P01350

Gastrin releasing peptide Other Ligand P07492

Glucagon Secretins Ligand

Glutamate Amino Acids Ligand

Glycine Amino Acids Ligand

Growth hormone-releasing Secretins Ligand Q9UBU3 factor

Histamine Monoamines Ligand

Melatonin Monoamines Ligand

Motilin Secretins Ligand P12872

N- Acetylaspartylg I utam ate Neuropeptides Ligand

N-Arachidonoyl dopamine Endocannabinoid Ligand

N-methylphenethylamine Amines Ligand

N-methyltryptamine Amines Ligand

Neurokinin A Tachykinins Ligand P20366

Neurokinin B Tachykinins Ligand Q334E7 Accession

Ligand Pathway Type Number

Neuropeptide Y Neuropeptides Ligand P01303

Neurophysin 1 Neurohypophyseals Ligand P01 178

Neurophysin II Neurohypophyseals Ligand P01 185

Nitric oxide Gas Ligand

Norepinephrine Monoamines Ligand

Octopamine Amines Ligand

Orexin A Orexins Ligand 043612

Orexin B Orexins Ligand 043613

Oxytocin Neurohypophyseals Ligand

Pancreatic polypeptide Neuropeptides Ligand P01298

Peptide YY Neuropeptides Ligand P10082

Phenethylamine Amines Ligand

Serotonin Monoamines Ligand

Somatostatin Somatostatins Ligand P61278

Substance P Neuropeptides Ligand

Synephrine Amines Ligand

Tryptamine Amines Ligand

Tyramine Amines Ligand

Vasoactive intestinal Secretins P01282

Ligand

peptide

Vasopressin Neurohypophyseals Ligand

Virodhamine Endocannabinoid Ligand

TABLE 1 C: NEURONAL GROWTH FACTORS

Gene Type Accession Entrez

Number Gene ID

ARTN Ligand Q5T4W7 9048

BDNF Ligand P23560 627

BDNF-AS Ligand 497258

BEX1 Signaling Q9HBH7 55859

BEX3 Signaling Q00994 27018

CD34 Receptor P28906 947

CDNF Ligand Q49AH0 441549

CNTF Ligand P26441 1270

CNTFR Receptor P26992 1271

CRLF1 Receptor 075462 9244

CSPG5 Ligand 095196 10675

DCLK1 Signaling 015075 9201 Gene Type Accession Entrez Number Gene ID

DISC1 Signaling Q9NRI5 27185

DNAJC5 Signaling Q9H3Z4 80331

DPYSL2 Signaling Q16555 1808

DVL1 Signaling 014640 1855

EFNA5 Ligand P52803 1946

EGR3 Signaling Q06889 1960

EN02 Signaling P09104 2026

EphA1 Receptor P21 709 2041

EphAI O Receptor Q5JZY3 284656

EphA2 Receptor P29317 1969

EphA3 Receptor P29320 2042

EphA4 Receptor P29317 2043

EphA5 Receptor P54756 2044

EphA6 Receptor Q9UF33 285220

EphA7 Receptor Q15375 2045

EphA8 Receptor P29322 2046

EphB1 Receptor P54762 2047

EphB2 Receptor P29323 2048

EphB3 Receptor P54753 2049

EphB4 Receptor P54760 2050

EphB6 Receptor 015197 2051

ETBR2 Receptor 060883 9283

FSTL4 Receptor Q6MZW2 23105

GDNF Ligand P39905 2668

GFRA1 Receptor P56159 2674

GFRA2 Receptor 000451 2675

GFRA3 Receptor 060609 2676

GFRA4 Receptor Q9GZZ7 64096

GPR37 Receptor 015354 2861

GPRIN1 Signaling Q7Z2K8 1 14787

GPRIN2 Signaling 060269 9721

GPRIN3 Signaling Q6ZVF9 285513

GRB2 Signaling P62993 2885

GZF1 Signaling Q9H1 16 64412

IFNA1 Ligand P01 562 3439

IGF1 Ligand P05019 3479

IGF2 Ligand P01344 3481

IL1 1 RA Receptor Q14626 3590 Gene Type Accession Entrez Number Gene ID

IL1 B Ligand P01 584 3553

IL3 Ligand P08700 3562

IL4 Ligand P051 12 3565

IL6 Ligand P05231 3569

IL6R Receptor P08887 3570

IL6ST Signaling P40189 3572

INS Ligand P01308 3630

L1 CAM Signaling P32004 3897

LIF Ligand P15018 3976

LIFR Receptor P42702 3977

MAGED1 Signaling Q9Y5V3 9500

MANF Ligand P55145 7873

NDNF Ligand Q8TB73 79625

NENF Ligand Q9UMX5 29937

NENFP1 Ligand 106480294

NENFP2 Ligand 100129880

NENFP3 Ligand 106481703

NGF Ligand P01 138 4803

NGFR Receptor P08138 4804

NRG1 Ligand Q02297 3084

NRP1 Receptor 014786 8829

NRTN Ligand Q99748 902

NTF3 Ligand P20783 4908

NTF4 Ligand P34130 4909

NTRK1 Receptor P04629 4914

NTRK2 Receptor Q16620 4915

NTRK3 Receptor Q16288 4916

PDPK1 Signaling 015530 5170

PEDF Ligand P36955 5176

PLEKHH3 Signaling Q7Z736 79990

PSAP Ligand P07602 5660

PSEN1 Signaling P49768 5663

PSPN Ligand 070300 5623

PTN Ligand P21 246 5764

RELN Ligand P78509 5649

RET Signaling P07949 5979

R0R1 Receptor Q01973 4919

R0R2 Receptor Q01974 4920 Gene Type Accession Entrez

Number Gene ID

RPS6KA3 Signaling P51 812 6197

SDC3 Receptor 075056 9672

SEMA3E Ligand 015041 9723

SERPINE2 Ligand P07093 5270

SERPINF1 Ligand P36955 5176

SHC1 Signaling P51 812 6464

SNTG1 Biosynthesis P07602 54212

SORCS1 Receptor 075056 1 14815

SORCS2 Receptor 015041 57537

SORCS3 Receptor P07093 22986

SORT1 Receptor Q99523 6272

SULF1 Signaling Q8IWU6 23213

SULF2 Signaling Q8IWU5 55959

TGFB1 Ligand P01 137 7040

TGFB2 Ligand P61 812 7042

TGFB3 Ligand P10600 7043

TMEM158 Receptor Q8WZ71 25907

TNF Ligand P01375 7124

TPM3 Receptor P06753 7170

VEGFA Ligand P15692 7422

VEGFB Ligand P49765 7423

VGF Ligand 015240 7425

XCR1 Receptor P46094 2829

ZN274 Signaling Q96GC6 10782

Neurotransmission modulators

In some embodiments, the neuromodulating agent is a neurotransmission modulator (e.g., an agent that increases or decreases neurotransmission). For example, in some embodiments, the neuromodulating agent is a neurotransmitter or neurotransmitter receptor listed in Table 1 A, 1 B, Table 7, or Table 8, a modulator of a channel or transporter encoded by a gene in Table 7, or an agonist or antagonist listed in Tables 2A-2K for a corresponding neurotransmitter pathway member. In some embodiments, the neurotransmission modulator is a neurotransmission modulator listed in Table 2M. Neuromodulating agents that increase neurotransmission include neurotransmitters and neurotransmitter receptors listed in Tables 1 A, 1 B, Table 7, and Table 8 and analogs thereof, and neurotransmitter agonists (e.g., small molecules that agonize a neurotransmitter receptor listed in Table 1 A or encoded by a gene in Table 7 or Table 8). Exemplary agonists are listed in Tables 2A-2K. In some embodiments, neurotransmission is increased via administration, local delivery, or stabilization of neurotransmitters (e.g., ligands listed in Tables 1 A, 1 B, and Table 7). Neurotransmission modulators that increase neurotransmission also include agents that increase neurotransmitter synthesis or release (e.g., agents that increase the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, or upregulation, or agents that increase the activity of a synaptic or vesicular protein encoded by a gene in Table 7 via stabilization, overexpression, or upregulation), prevent neurotransmitter reuptake or degradation (e.g., agents that block or antagonize transporters encoded by a gene in Table 7 or Table 8 that remove neurotransmitter from the synaptic cleft), increase

neurotransmitter receptor activity (e.g., agents that increase the activity of a signaling protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, agonism, or upregulation, or agents that upregulate, agonize, or stabilize a neurotransmitter receptor listed in Table 1 A or encoded by a gene in Table 7 or Table 8), increase neurotransmitter receptor synthesis or membrane insertion, decrease neurotransmitter degradation, and regulate neurotransmitter receptor conformation (e.g., agents that bind to a receptor and keep it in an "open" or "primed" conformation). In some embodiments, the

neurotransmitter receptor is a channel (e.g., a ligand or voltage gated ion channel listed in Table 7 or Table 8), the activity of which can be increased by agonizing, opening, stabilizing, or overexpressing the channel. Neurotransmission modulators that increase neurotransmission further include agents that stabilize a structural protein encoded by a gene in Table 7. Neurotransmission modulators can increase neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. Exemplary neurotransmission modulators are listed in Table 2M.

Neuromodulating agents that decrease neurotransmission include neurotransmitter antagonists

(e.g., small molecules that antagonize a neurotransmitter receptor listed in Table 1 A or Table 7 or Table 8). Exemplary antagonists are listed herein below and in Tables 2A-2K. Neurotransmission modulators that decrease neurotransmission also include agents that decrease neurotransmitter synthesis or release (e.g., agents that decrease the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via inhibition or downregulation, or agents that decrease the activity of a synaptic or vesicular protein encoded by a gene in Table 7 via blocking, disrupting, or downregulating, or antagonizing the protein), increase neurotransmitter reuptake or degradation (e.g., agents that agonize, open, or stabilize transporters encoded by a gene in Table 7 or Table 8 that remove neurotransmitter from the synaptic cleft), decrease neurotransmitter receptor activity (e.g., agents that decrease the activity of a signaling protein encoded by a gene in Table 1 A or Table 7 via blocking or antagonizing the protein, or agents that block, antagonize, or downregulate a neurotransmitter receptor listed in Table 1 A or encoded by a gene in Table 7 or Table 8), decrease neurotransmitter receptor synthesis or membrane insertion, increase neurotransmitter degradation, regulate neurotransmitter receptor conformation (e.g., agents that bind to a receptor and keep it in a "closed" or "inactive" conformation), and disrupt the pre- or postsynaptic machinery (e.g., agents that block or disrupt a structural protein encoded by a gene in Table 7, or agents that block, disrupt, downregulate, or antagonize a synaptic or vesicular protein encoded by a gene in Table 7). In some embodiments, the neurotransmitter receptor is a channel (e.g., a ligand or voltage gated ion channel listed in Table X or Table X.1 ), the activity of which can be decreased by blockade, antagonism, or inverse agonism of the channel. Neurotransmission modulators that decrease neurotransmission further include agents that sequester, block, antagonize, or degrade a

neurotransmitter listed in Tables 1 A, 1 B, or encoded by a gene in Table 7. Neurotransmission modulators that decrease or block neurotransmission include antibodies that bind to or block the function of neurotransmitters, neurotransmitter receptor antagonists, and toxins that disrupt synaptic release. Neurotransmission modulators can decrease neurotransmission by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.

In some embodiments, the neuromodulating agent is an adrenergic receptor pathway modulator (e.g., a blocker or agonist of an adrenergic receptor listed in Table 1 A or Table 7, e.g., an adrenergic blocker or agonist listed in Table 2A or Table 2B); a cholinergic receptor pathway modulator (e.g., a blocker or agonist of a cholinergic receptor listed in Table 1 A or Table 7, e.g., a cholinergic blocker or agonist listed in Table 2A, 2E, or 2F); a dopamine receptor pathway modulator (e.g., a blocker or agonist of a dopamine receptor listed in Table 1 A or Table 7, e.g., a dopamine blocker or agonist listed in Table 2A or 2C); a serotonin receptor pathway modulator (e.g., a blocker or agonist of a serotonin receptor listed in Table 1 A, Table 7, or Table 8, e.g., a serotonin blocker or agonist listed in Table 2A or 2G); a GABA receptor pathway modulator (e.g., a blocker or agonist of a GABA receptor listed in Table 1 A, Table 7, or Table 8, e.g., a GABA blocker or agonist listed in Table 2A or 2D); a glutamate receptor pathway modulator (e.g., a blocker or agonist of a glutamate receptor listed in Table 1 A, Table 7, or Table 8, e.g., a glutamate blocker or agonist listed in Table 2A or 2H).

TABLE 2A: AGONIST AND ANTAGONIST AGENTS

Gene Agonist Antagonist

Clenbuterol

Bambuterol

Indacaterol

Droxidopa

Olodaterol

Vilanterol

Pseudoephedrine

Cabergoline

Mirtazepine

Ad raid Midodrine Dapiprazole

Accession Number: Norepinephrine Amitriptyline

P25100 Clonidine Alfuzosin

Oxymetazoline Promazine

Pergolide Prazosin

Bromocriptine Imipramine

Droxidopa Nortriptyline

Xylometazoline Doxazosin

Ergotamine Nicardipine

Cirazoline Dronedarone

Cabergoline Tamsulosin

Methoxamine Propiomazine

Epinephrine Phenoxybenzamine

Carvedilol

Doxepin

Terazosin

Quetiapine

Methotrimeprazine

Silodosin

Adrbl Isoetarine Esmolol

Accession Number: Norepinephrine Betaxolol Gene Agonist Antagonist

P08588 Phenylpropanolamine Metoprolol

Epinephrine Atenolol

Dobutamine Timolol

Salbutamol Sotalol

Isoprenaline Propranolol

Arbutamine Labetalol

Fenoterol Bisoprolol

Pirbuterol Alprenolol

Ephedra Amiodarone

Clenbuterol Carvedilol

Droxidopa Nadolol

Pseudoephedrine Levobunolol

Carteolol Metipranolol

Cabergoline Bevantolol

Mirtazapine Practolol

Loxapine Oxprenolol

Vortioxetine Celiprolol

Desipramine Nebivolol

Asenapine

Bupranolol

Penbutolol

Pindolol

Acebutolol

Bopindolol

Cartelol

Ad ib 3 SR 5861 1 Bopindolol

Accession Number: Norepinephrine Propranolol

P13945 Epinephrine Bupranolol

Isoprenaline

Arbutamine

Fenoterol

Ephedra

Clenbuterol

Droxidopa

Mirabegron Gene Agonist Antagonist

Ad bkl ATP Alprenolol

Accession Number: Carbachol Heparin

P25098 Dopamine

Isoproterenol

Morphine

DAMGO

histamine

Acetylcholine

Etorphine

NMDA

Dopamine

Ad ib k 2 Isoproterenol Propranolol

Accession Number: DAMGO

P26819 ATP

cgmp MT3

Chrm3

ATP hexocyclium

Accession Number:

Cevimeline himbacine

P20309

arecoline Biperiden oxotremorine-M lithocholylcholine

NNC 1 1 -1314 AFDX384 xanomeline 4-DAMP oxotremorine hexahydrodifenidol pentylthio-TZTP VU0255035 arecaidine propargyl ester N-methyl scopolamine

NNC 1 1 -1607 darifenacin furmethide Thiethylperazine

NNC 1 1 -1585 methoctramine

Acetylcholine silahexocyclium methylfurmethide strychnine

Bethanechol MT7

Carbachol Heparin

Succinylcholine Olanzapine

ALKS 27 Pirenzepine itopride Clidinium Gene Agonist Antagonist

methacholine Ipratropium

Meperidine Propantheline

Cinnarizine Dicyclomine

Trimipramine Darifenacin

Tiotropium

Atropine

Scopolamine

Amitriptyline

Doxepin

Lidocaine

Nortriptyline

Tropicamide

Metixene

Homatropine Methylbromide

Solifenacin

Glycopyrrolate

Propiomazine

Diphemanil Methylsulfate

Promethazine

Diphenidol

Pancuronium

Ziprasidone

Quetiapine

Imipramine

Clozapine

Cyproheptadine

Aripiprazole

Nicardipine

Amoxapine

Loxapine

Promazine

Oxyphencyclimine

Anisotropine Methylbromide

Tridihexethyl

Chlorpromazine

Ketamine

Cyclosporin A

Paroxetine

Benzquinamide Gene Agonist Antagonist

Tolterodine

Oxybutynin alcuronium

WIN 62,577

Tramadol

Chlorprothixene

Aclidinium

Methotrimeprazine

Umeclidinium

Cryptenamine

Mepenzolate

Maprotiline

Brompheniramine

Isopropamide

Trihexyphenidyl

Ipratropium bromide

Hyoscyamine

Procyclidine

Pipecuronium

Fesoterodine

Disopyramide

Desipramine

Mivacurium

Chrna3 Nicotine A-867744

Accession Number: Varenicline NS1738

P32297 Acetylcholine Hexamethonium

Ethanol Mecamylamine

Cytisine Dextromethorphan

Levamisole Pentolinium

Galantamine Levomethadyl Acetate

Bupropion

Chrna6 Nicotine Hexamethonium

Accession Number: Cytisine Mecamylamine

Q15825 Varenicline

Galantamine Gene Agonist Antagonist

Chrna9 Nicotine Hexamethonium

Accession Number: Galantamine Mecamylamine

Q9UGM1 Ethanol Tetraethylammonium

Muscarine

ATG003 Strychnine

Lobeline

RPI-78M

Chrnbl Galantamine

Accession Number:

P11230

Chrnb4 Nicotine Atropine

Accession Number: Varenicline Oxybutynin

P30926 PNU-120596 Pentolinium

Ethanol Dextromethorphan

Galantamine

Chrng Galantamine

Accession Number:

P07510

Adcyapl Nicotine Atropine

Accession Number: CGMP PPADS

P18509 Apomorphine Onapristone

Suramin Muscarine

Nifedipine Haloperidol

ATP Astressin

Dihydrotestosterone Melatonin

Maxadilan Scopolamine

Dexamethasone Tetrodotoxin

Acetylcholine Apamin

Histamine Hexamethonium

Carbachol Indomethacin

NMDA Propranolol

Dopamine Bumetanide

Isoproterenol Progesterone Gene Agonist Antagonist

Salbutamol Charybdotoxin

Morphine Prazosin

Clonidine

Nimodipine

2,6-Diamino-Hexanoic Acid Amide

AVPR1 B dVDAVP YM 218

Accession Number: LVP Tolvaptan

P47901 dAVP Atosiban

Oxytocin SSR149415

Desmopressin YM 471

Vasopressin OH-LVA

Terlipressin Satavaptan

SR 121463

PH-284

CALCB Amylin MK-0974

Accession Number:

P10092

Omeprazole devazepide

Caffeine Methysergide

Hydrocortisone Cyproheptadine cholesterol Naloxone lauric acid lorglumide

Dexamethasone Atropine

CCK

NAADP Rimonabant

Accession Number:

P06307 Octreotide Raclopride decanoic acid Nicardipine

Dopamine Pirenzepine

Vapreotide Ranitidine

Acetylcholine chenodeoxycholic histamine Dexloxiglumide

Carbachol Tetrodotoxin

Bethanechol Diltiazem

Tegaserod Aspirin

Cisapride Fenfluramine Gene Agonist Antagonist

Morphine Cyclosporin A

CPE Dopamine

Accession Number: Insulin, porcine

P16870 Insulin Regular

CRHBP Hydrocortisone Progesterone

Accession Number: Dexamethasone Astressin

P24387 Sauvagine

CYSLTR1 Salbutamol Montelukast

Accession Number: Dexamethasone Zafirlukast

Q9Y271 Arachidonic acid Cinalukast

Histamine Pranlukast

Nedocromil

Theophylline

Indomethacin

Zileuton iralukast pobilukast sulukast verlukast

CGMP Colchicine

GAL

ATP Naloxone

Accession Number:

Capsaicin Atropine

P22466

Galnon Melatonin

Dexamethasone Tetrodotoxin

Levodopa Reserpine

Acetylcholine Glyburide

Hexarelin tetraethylammonium

Histamine

Carbachol

Octreotide

Dopamine

Salbutamol Gene Agonist Antagonist

Morphine

Clonidine

Bromocriptine

GALR3 galanin C7

Accession Number: galanin-like peptide M15

060755 galnon M32

J18 (galanin analogue) M35

J20 (galanin analogue) M40

M1 145 M871

M1 151 SNAP 37889

M1 152 SNAP 398299

M1 153

M1 160

M617

GRP Nicotine Tamoxifen

Accession Number: Diazoxide Atropine

P11021 Genistein Pirenzepine

Nifedipine Cetrorelix

Capsaicin BIM 23127

Caffeine Tetrodotoxin

Hydrocortisone Aspirin

Dexamethasone Glyburide

NAADP Propranolol

Isoproterenol Indomethacin

NMDA

ranatensin

Bombesin

Bethanechol

Octreotide

Acetylcholine

phyllolitorin

Carbachol

Dopamine

histamine

arachidonic acid Gene Agonist Antagonist

LTB4R LTB U75302

Accession Number: ATP CP105696

Q15722 Dexamethasone CP-195543 cholesterol etalocib

20-hydroxy-LTB< SC-41930

12R-HETE LY255283 arachidonic acid Zafirlukast

ONO-4057

RO5101 576

BILL 260

NMU EUK201 0 R-PSOP

Accession Number: EUK201 1

Q9GZQ4 EUK2012

NPM Ornithine Dipyridamole

Accession Number: ATP

P06748

NPBWR1 NPW-23 CYM50769

Accession Number: des-Br-NPB-23

P48145 Ava3

Ava5

des-Br-neuropeptide B-23

des-Br-neuropeptide B-29

neuropeptide B-29

neuropeptide W-23

neuropeptide W-30

NPW Neuropeptide W-23

Accession Number:

Q8N729

NPY Nicotine BIIE0246

Accession Number: Nifedipine Heparin Gene Agonist Antagonist

P01303 Capsaicin Theophylline

ATP Sulpiride

Prednisolone BIBO3304

Bethanechol BIBP3226

Phenylephrine Atropine

Acetylcholine Naltrexone histamine Yohimbine

Octreotide Phentolamine kainate Haloperidol

Muscimol Tetrodotoxin

NMDA phencyclidine

Carbachol Fenfluramine

Methoxamine Indomethacin

Isoproterenol Reserpine arpromidine Prazosin

Dopamine

Clonidine

Pilocarpine

L-Tyrosinamide

2-Aminoisobutyric acid

NPY5R PYY3-36 L-152,804

Accession Number: NPY-(18-36) BIBP3226

Q15761 PYY Velneperit

NPY FMS586 histamine BIIE0246

PYY-(3-36)

PYY-(3-36)

pancreatic polypeptide

Acetylcholine

AC162352

NTS Apomorphine Olanzapine

Accession Number: oleic acid Melatonin

Q6FH20 Nicotine Yohimbine

Nifedipine Thioridazine

Capsaicin Diphenhydramine

ATP Haloperidol Gene Agonist Antagonist

Dexamethasone SR142948A

Levodopa Sulpiride triamcinolone acetonide Naloxone neurotensin Heparin

QUINPIROLE Atropine kainate Clozapine histamine apamin

Carbachol Tetrodotoxin

NMDA Anandamide

Isoproterenol Chlorpromazine

Acetylcholine phencyclidine

Dopamine Reserpine

Dexmedetomidine Indomethacin

Octreotide Bumetanide

Levocabastine

Clonidine

Morphine

arachidonic acid

NTSR1 JMV2004 Meclinertant

Accession Number: JMV431 SR142948A

P30989 JMV457

JMV458

Levocabastine

large neuromedin N

large neurotensin

Dopamine

neurotensin

contulakin-G

KH28

PENK Dopamine Naltrexone

Accession Number: kainate Naloxone

P01210 NMDA Progesterone

DAMGO

Morphine Gene Agonist Antagonist

PNOC Capsaicin Atropine

Accession Number: ACONITINE Naloxone

Q13519 Etorphine Naltrexone histamine Buprenorphine

NMDA naltrindole

Acetylcholine hexamethonium

Dopamine Anandamide

DAMGO DPDPE

Morphine Progesterone

PTH2R Ostabolin-C PTH-(7-34)

Accession Number: Teriparatide PTHrP-(5-36)

P49190 Preotact TIP39

SCG2 ATP

Accession Number: Capsaicin

P13521 Dexamethasone

histamine

Acetylcholine

Dopamine

SCG5 ATP Farnesyl diphosphate

Accession Number: Cholesterol Heparin

P05408 Dexamethasone

NMDA

histamine

SSTR1 CST-14

Accession Number: Octreotide

P30872 Pasireotide

SSTR2 Octreotide Progesterone

Accession Number: Dopamine Tamoxifen

P30874 Pasireotide Gene Agonist Antagonist

UCN2 Dopamine

Accession Number: Acetylcholine

Q96RP3 histamine

Sauvagine

UTS2 lysophosphatidylcholine palosuran

Accession Number: cholesterol Atropine

095399 Acetylcholine Tetrodotoxin

Phenylephrine Indomethacin

Verapamil

cgmp Melatonin

VIP

Suramin Sumatriptan

Accession Number:

Capsaicin Phentolamine P01282

Capsaicin Naloxone

Caffeine Haloperidol

Nifedipine Astressin cromakalim Atropine maxadilan Tetrodotoxin

Dexamethasone apamin

Prednisolone hexamethonium

BAY 55-9837 Amiloride

Dihydrotestosterone Thiorphan carbacyclin Indomethacin

Citrulline Cyclosporin

Carbachol Verapamil histamine Propranolol

Dopamine Bumetanide

Phenylephrine Captopril

Acetylcholine Sildenafil

Octreotide Glyburide

Methoxamine tetraethylammonium

Isoproterenol

Ephedrine

Salbutamol Gene Agonist Antagonist

Bromocriptine

Morphine

VIPR1 PHM Secretin

Accession Number: BAY 55-9837 neurotensin-(6-1 1 )/VIP-(7-28)

P32241

helodermin

PACAP-27

VIP

PACAP-38

PG 99-465

PHI

PHI

PHV

Ro 25-1392

Apomorphine Melatonin

Htr2c

Bifeprunox SB 224289

Accession Number:

Tramadol LY334362

P28335

AL-37350A FR260010

5-MeO-DMT Sulpiride

BW723C86 Thiethylperazine

CGS-12066 cyamemazine

DOI mesulergine

5-CT SB 221284

YM348 zotepine

LSD Metergoline xanomeline methiothepin

WAY-163909 spiperone

Dopamine SB 215505

LY344864 tiospirone

VER-3323 SB 228357

TFMPP pizotifen

8-OH-DPAT SB 206553

MK-212 SB 204741

NMDA SDZ SER-082 org 12962 Ritanserin

5-MeOT SB 242084 Gene Agonist Antagonist

RU 24969 S33084

Acetylcholine roxindole

QUINPIROLE RS-127445 quipazine terguride tryptamine EGIS-7625

Ro 60-0175 SB 243213

Oxymetazoline RS-102221

Ergotamine Olanzapine

Cabergoline Aripiprazole

Lorcaserin Agomelatine

Pergolide Ziprasidone

Methylergonovine Quetiapine

Renzapride Sarpogrelate

Pramipexole Perphenazine

GR-127935 Thioridazine

BRL-15572 Sertindole ipsapirone Loxapine

SB 216641 Methysergide

SL65.0155 Risperidone

S 16924 Asenapine

Bromocriptine Mianserin

Lisuride Clozapine

Tegaserod Trifluoperazine

Epicept NP-1 Trazodone dapoxetine Doxepin

Dexfenfluramine Nortriptyline

3,4- Chlorprothixene

Methylenedioxymethamphetamine

Ropinirole Minaprine

Maprotiline Propiomazine

Desipramine Mirtazapine

Amoxapine

Yohimbine

Cyproheptadine

Imipramine

Amitriptyline

Promazine

Chlorpromazine

Ketamine Gene Agonist Antagonist

Propranolol

Fluoxetine

Ketanserin mesulergine

AC-90179

Ergoloid mesylate 2

Methotrimeprazine

Paliperidone

Clomipramine

Trimipramine

Captodiame

Nefazodone

Bamaluzole bicuculline

GABA Receptor

Accession Numbers

GABA metrazol (Q9UBS5, 095166,

Gabamide flumazenil 075899, P28472, P1 8507,

GABOB thiothixine P47870, P47869, 014764)

Gaboxadol bupropion

Ibotenic acid caffeine

Isoguvacine

Isonipecotic acid

Muscimol

Phenibut

Picamilon

Progabide

Quisqualamine

SL 75102

Thiomuscimol

Alcohols (e.g., ethanol, isopropanol)

Avermectins (e.g., ivermectin)

Barbiturates (e.g., phenobarbital)

Benzodiazepines

Bromides (e.g., potassium bromide

Carbamates (e.g., meprobamate,

carisoprodol)

Chloralose

Chlormezanone Gene Agonist Antagonist

Clomethiazole

Dihydroergolines (e.g., ergoloid

(dihydroergotoxine))

Etazepine

Etifoxine

Imidazoles (e.g., etomidate)

Kavalactones (found in kava)

Loreclezole

Neuroactive steroids (e.g.,

allopregnanolone, ganaxolone)

Nonbenzodiazepines (e.g.,

zaleplon, Zolpidem, zopiclone,

eszopiclone)

Petrichloral

Phenols (e.g., propofol)

Piperidinediones (e.g., glutethimide,

methyprylon)

Propanidid

Pyrazolopyridines (e.g., etazolate)

Quinazolinones (e.g.,

methaqualone)

Skullcap constituents

Stiripentol

Sulfonylalkanes (e.g.,

sulfonmethane, tetronal, trional)

Valerian constituents (e.g., valeric

acid, valerenic acid)

Volatiles/gases (e.g., chloral

hydrate, chloroform, diethyl ether,

sevoflurane)

3,5-dihydroxyphenylglycine APICA

Glutamate Receptor

Accession Number:

(P42261 , P39086,

P39086, Q13585, P42261 ,

P42262, P42263, P48058, eglumegad EGLU

P39086, Q13002, Biphenylindanone A LY-341 ,495

Q13003, Q13003, DCG-IV

Q16478, Q12879, L-AP4 Gene Agonist Antagonist

Q14957, Q13224,

Q14957, 015399,

Q8TCU5, 060391 )

CNR1 /CNR2 N-Arachidonoylethanolamine SR 141716A Accession Number: 2-Arachidonoyl -glycerol LY-320135 (P21554, P34972) 2-Arachidonoyl-glycerylether AM251

N-Arachidonoyl-dopamine AM281

O-Arachidonoyl-ethanolamine SR 144528

N-Arachidonoylethanolamine AM630

2-Arachidonoyl -glycerol

2-Arachidonoyl-glycerylether

N-Arachidonoyl-dopamine

O-Arachidonoyl-ethanolamine

Δ 9-THC

CP-55,940

R(+)-WIN 55,212-2

HU-210

Levonantradol

Nabilone

Methanandamide

ACE A

0-1812

A9-THC

CP-55,940

R(+)-WIN 55,212-2

HU-210

Levonantradol

Nabilone

Methanandamide

JWH-015

JWH-133

TABLE 2B: ADRENERGIC AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist Receptor Agonist Antagonist

Non-selective Adrenaline (epinephrine), Carvedilol, arotinolol, and

Noradrenaline (norepinephrine), labetalol

Isoprenaline (isoproterenol),

dopamine, caffeine, nicotine,

tyramine, methylphenidate,

ephedrine and pseudophedrine. crt selective (ADRA1 A, ADRA1 B, Phenylephrine, methoxamine, Acepromazine, alfuzosin, ADRA1 D) midodrine, cirazoline, doxazosin, labetalol,

Xylometazoline, metaraminol phenoxybenzamine, KW3902, Chloroehtylclonidine, phentolamine, prazosin, oxymetazoline tamsulosin, terazosin, tolazoline, trazodone, amitriptyline, silodosin, clomipramine, doxepin, trimipramine, typical and atypical antipsychotics, and

antihistamines, such as hyroxyzine

a2 selective (ADRA2A, ADRA2B, A-methyl dopa, clonidine, Phentolamine,

ADRA2C) Brimonidine, agmatine, phenoxybenzamine, yohimbine,

Dexmedetomidine, idazoxan, atipamezole,

Medetomidine, romifidine mirtazapine, tolazoline,

Chloroethylclonidine, trazodone, and typical and Detomidine, lofexidine, xylazine, atypical antipsychotics

Tizanidine, guanfacine, and

amitraz

β1 selective (ADRB1 ) Dobutamine Metroprolol, atenolol, acebutolol, bisoprolol, betaxolol, levobetaxolol, esmolol, celiprolol, carteolol, landiolol, oxprenolol, propanolol, practolol, penbutolol, timolol, labetalol, nebivolol, levobunolol, nadolol, pindolol, sotalol, metipranolol, tertatolol, vortioxene

β2 selective (ADRB2) Salbutamol, albuterol, bitolterol Butaxamine, acebutolol, timolol, mesylate, levabuterol, ritodrine, propanolol, levobunolol, metaproterenol, terbutaline, carteolol, labetalol, pindolol, salmeterol, formoterol, and oxprenolol, nadolol, metipranolol, pirbuterol penbutolol, tertatolol, sotalol Receptor Agonist Antagonist

β3 selective (ADRB3) L-796568, amibegron, SR 59230A, arotinolol

solabegron, mirabegron

TABLE 2C: DOPAMINE AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

Non-selective Pramipexole, ropinirole, Haloperidol, paliperidone,

rotigotine, apomorphine, clozapine, risperidone, propylnorapomorphine, olanzapine, quetiapine, bromocriptine, cabergoline, ziprasidone, metoclopramide, ciladopa, dihydrexidine, droperidol, dromperidone, dinapsoline, doxamthrine, amoxapine, clomipramine, epicriptine, lisuride, pergolide, trimipramine, choline, melatonin, piribedil, quinagolide, roxindole, acepromazine, amisulpride, dopamine asenapine, azaperone,

benperidol, bromopride, butaclamol, chlorpromazine, chlorprothixene, clopenthixol, eticlopride, flupenthixol, fluphenazine, fluspirilene, hydroxyzine, iodobenzamide, levomepromazine, loxapine, mesoridazine, nafadotride, nemonapride, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, raclopride, remoxipride, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone

D1 (DRD1 ) Fenoldopam, A-86929, Sch-23,390, skf-83,959,

dihydrexidine, dinapsoline, ecopipam

dinoxyline, doxanthrine, SKF-

81297, SKF-82958, SKF-38393,

G-BR-APB, dopexamine

D2 (DRD2) Cabergoline, pergolide, Chloroethylnorapomorphine, Receptor Agonist Antagonist

quinelorane, sumanirole, desmethoxyfallypride, talipexole, piribedil, quinpirole, domperidone, eticlopride, quinelorane, dinoxyline, fallypride, hydroxyzine, itopride, dopexamine L-741 ,626, SV 293, yohimbine, raclopride, sulpiride,

D3 (DRD3) Piribedil, quinpirole, captodiame, Domperidone, FAUC 365,

compound R, R-16, FAUC 54, nafadotride, raclopride, PNU- FAUC 73, PD-128,907, PF- 99,194, SB-27701 1 -A, sulpiride, 219,061 , PF-592,379, CJ-1037, risperidone, YQA14, U99194, SR FAUC 460, FAUC 346, 21502

cariprazine

D4 (DRD4) Way-100635, a-412,997, abt- A-381393, FAUC 213, L- 724, abt-670, fauc 316, pd-168, 745,870, L-570,667, ML-398, 077, cp-226,269 fananserin, clozapine

D5 (DRD5) Dihydrexidine, rotigotine, SKF- Sch 23390

83,959, fenoldopam,

Partial Aplindore, brexpiprazole,

aripiprazole, CY-208,243,

pardoprunox, phencyclidine, and

salvinorin A

TABLE 2D: GABA AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

GABAA Barbiturates (e.g., allobarbital, Bicuculline, gabazine, hydrastine, amobarbital, aprobarbital, pitrazepin, sinomenine, tutin, alphenal, barbital, brallobarbital, thiocolchicoside, metrazol, phenobarbital, secobarbital, securinine, gabazine

thiopental), bamaluzole, gaba,

gabob, gaboxadol, ibotenic acid,

isoguvacine, isonipecotic acid,

muscimol, phenibut, picamilon,

progabide, quisqualamine, si

75102, thiomuscimol, positive

allosteric modulators (pams)

(e.g., alcohols, such as ethanol

and isopropanol; avermectins,

such as ivermectin;

benzodiazepines, such as Receptor Agonist Antagonist diazepam, alprazolam,

chlordiazepoxide, clonazepam,

flunitrazepam, lorazepam,

midazolam, oxazepam,

prazepam, brotizolam, triazolam, estazolam, lormetazepam,

nitrazepam, temazepam,

flurazepam, clorazepate

halazepam, prazepam,

nimetazapem, adinazolam, and

climazolam ; bromides, such as

potassium bromide; carbamates, such as meprobamate and

carisoprodol; chloralose;

chlormezanone; chlomethiazole;

dihydroergolines, such as

ergoloid; etazepine; etifoxine;

imidazoles, such as etomidate;

imidazopyridines, such as

alpidem and necopdiem ;

kavalactones; loreclezole;

neuroactive steroids, such as

allogregnanolone, pregnanolone, dihydrodeoxycorticosterone,

tetrahydrodeoxycortisosterone,

androstenol, androsterone,

etiocholanolone, 3a- androstanediol, 5a, 5β, or 3a- dihydroprogesterone, and

ganaxolone;

nonbenzodiazepines, such as

zalepon, Zolpidem, zopiclone,

and eszopiclone; petrichloral;

phenols, such as propofol;

piperidinediones, such as

glutethimide and methyprylon;

propanidid; pyrazolopyridines,

such as etazolate;

pyrazolopyrimidines, such as

divaplon and fasiplon; Receptor Agonist Antagonist

cyclopyrrolones, sush as

pagoclone and suproclone; β- cabolines, such as abecarnil and

geodecarnil; quinazolinones,

such as methaqualone;

Scutellaria constituents;

stiripentol; sulfonylalkanes, such

as sulfonomethane, teronal, and

trional; valerian constituents,

such as valeric acid and

valerenic acid; and gases, such

as chloral hydrate, chloroform,

homotaurine, diethyl ether, and

sevoflurane.

GABAB 1 ,4-butanediol, baclofen, GABA, CG P-35348, homotaurine,

Gabamide, GABOB, gamma- phaclofen, saclofen, and SCH- butyrolactone, gamma- 5091 1

hydroxybutyric acid, gamma- hyrdoxyvaleric acid, gamma- valerolactone, isovaline,

lesogaberan, phenibut,

picamilon, progabide,

homotaurine, SL-75102,

tolgabide

GABAA-P CACA, CAMP, GABA, GABOB, Gabazine, gaboxadol,

N4-chloroacetylcytosine isonipecotic acid, SKF-97,541 , arabinoside, picamilon, and (1 ,2,5,6-Tetrahydropyridin-4- progabide, tolgabide, and yl)methylphosphinic acid neuroactive steroids, such as

allopregnanolone, THDOC, and

alphaxolone

TABLE 2E: MUSCARINC AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

Chrml AF1 02B, AF150(S), AF267B, Atropine, dicycloverine,

acetylcholine, carbachol, hyoscyamine, ipratropium, cevimeline, muscarine, mamba toxin muscarinic toxin 7 oxotremorine, pilocarpine, (mt7)> olanzapine, oxybutynin, vedaclidine, 77-LH-28-1 , CDD- pirenzepine, telenzepine, and Receptor Agonist Antagonist

0097, mcn-A-343, L689.660, and tolterodine

xanomeline

Chrm2 Acetylcholine, methacholine, Atropine, dicycloverine,

iper-8-naph, berbine, and hyoscyamine.otenzepad, aqra- (2S,2'R,3'S,5'R)-1 -methyl-2-(2- 741 , afdx-384, thorazine, methyl-1 ,3-oxathiolan-5- diphenhydramine,

yl)pyrrolidine 3-sulfoxide methyl dimenhydrinate, ipratropium, iodide oxybutynin, pirenzepine,

methoctramine, tripitramine, gallamine, and tolterodine

Chrm3 Acetylcholine, bethanechol, Atropine, dicycloverine,

carbachol, L689, 660, hyoscyamine, alcidium bromide, oxotremorine, pilocarpine, 4-damp, darifenacin, dau-5884, aceclidine, arecoline, and hl-031 ,120, ipratropium, j- cevimeline 104,129, oxybutynin, tiotropium, zamifenacin, and tolterodine

Chrm4 Acetylcholine, carbachol, and Afdx-384, dicycloverine,

oxotremorine), and Chrm5 himbacine, mamba toxin 3, pd- agonists (e.g., acetylcholine, 102,807, pd-0298029, and milameline, sabcomeline tropicamide

Chrm5 Acetylcholine, milameline, Vu-0488130, xanomeline

sabcomeline

Non-selective Scopolamine, hydroxyzine, doxylamine, dicyclomine, flavoxate, cyclopentolate, atropine methonitrate, trihexyphenidyl/benzhexol, solifenacin, benzatropine, mebeverine, and procyclidine

TABLE 2F: NICOTINIC AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

Chrna receptors Choline, acetylcholine, Turbocurarine, bupropion, carbachol, methacholine, mecamylamine, 18- nicotine, varenicline tartrate, methozycoronaridine, galantamine hydrobromide, hexamethonium, trimethaphan, suxamethonium chloride atraciurium, doxacurium, (succinylcholine chloride), mivacurium, pancuronium, epibatidine, iobeline, vecuronium, succinylcholine, decamethonium, dextromethorphan, neramexane, isopronicline/TC-1734/AZD3480 dextrophan, and 3-

(TC-1734), AZD1446 (TC-6683), methoxymorphinan

TC-5619, TC-5214, MEM 3454

(RG3487), ABT-894, ABT-560,

EVP-6124, EVP-4473, PNU-

282987, AR-R17779, SSR

18971 1 , JN403, ABBF, PHA-

543613, SEN12333, GTS-

21 /DMXB-A, AZD0328, A-

582941 , ABT-418, 5-iodo-A-

85380, SIB-1765F, ABT-089, and

ABT-594

TABLE 2G: SEROTONIN AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

-HTiA Azapirones, such as alnespirone, Pindolol, tertatolol, alprenolol, binosperone, buspirone, AV-965, BMY-7,378, enilospirone, etapirone, geprione, cyanopindolol, dotarizine, ipsaprione, revospirone, flopropione, GR-46,61 1 , zalospirone, perospirone, iodocyanopindolol, isamoltane, tiosperone, umespirone, and lecozotan, mefway, methiothepin, tandospirone; 8-OH-DPAT, methysergide, MPPF, NAN-190, befiradol, F-15,599, lesopitron, oxprenolol, pindobind,

MKC-242, LY-283,284, propanolol, risperidone, osemozotan, repinotan, U- robalzotan, SB-649,91 5, SDZ- 92,016-A, RU-24969, 2C-B, 2C- 216,525, spiperone, spiramide, E, 2C-T-2, aripiprazole, spiroxatrine, UH-301 , WAY- asenapine, bacoside, befiradol, 100,135, WAY-100,635, and brexpiprazole, bufotenin, xylamidine

cannabidiol, and fibanserin

-HT1 B Triptans, such as sumatriptan, Methiothepin, yohimbine,

rizatriptan, eletriptan, donitripatn, metergoline, aripiprazole, almotriptan, frovatriptan, isamoltane, AR-A000002, SB- avitriptan, zolmitriptan, and 216,641 , SB-224,289, GR- naratriptan; ergotamine, 5- 127,935, SB-236,057 carboxamidotryptamine, CGS- 12066A, CP-93,129, CP-94,253,

CP-122,288, CP-135,807, RU- 24969, vortioxetine, ziprasidone,

and asenapine Receptor Agonist Antagonist

-HT1 D Triptans, such as sumatriptan, Ziprasidone, methiothepin,

rizatriptan, and naratriptan; yohimbine, metergoline, ergotamine, 5- ergotamine, BRL-1 5572,

(nonyloxy)tryptaime, 5-(t-butyl)- vortioxetine, GR-127,935, LY- N-methyltryptamine, CP-286,601 , 310,762, LY-367,642, LY- PNU-109,291 , PNU-142,633, 456,219, and LY-456,220 GR-4661 1 , L-694,247, L- 772,405, CP-122,288, and CP- 135,807

-HT1 E BRL-54443, eletriptan

-HT1 F LY-334,370, 5-n-butyryloxy-DMT,

BRL-54443, eletriptan, LY- 344,864, naratriptan, and

lasmiditan

-HT2A 25I-NBOH, 25l-nbome, (R)-DOI, Cyproheptadine, methysergide,

TCB-2, mexamine, 0-4310, quetiapine, nefazodone, PHA-57378, OSU-6162, 25CN- olanzapine, asenapine, pizotifen, NBOH, juncosamine, efavirenz, LY-367,265, AMDA, hydroxyzine, mefloquine, lisuride, and 2C-B 5-meo-nbpbrt, and niaprazine-HT2B Fenfluramine, pergolide, Agomelatine, aripiprazole,

cabergoline, mefloquine, BW- sarpogrelate, lisuride, tegaserod, 723C86, RO60-0175, VER-3323, metadoxine, RS-127,445, SDZ 6-APB, guanfacine, SER-082, EGIS-7625, PRX- norfenfluramine, 5-meo-DMT, 08066, SB-200,646, SB-204,741 , DMT, mcpp, aminorex, SB-206,553, SB-215,505, SB- chlorphentermine, MEM, MDA, 228,357, LY-266,097, and LY- LSD, psilocin, MDMA 272,015

-HT2C Lorcaserin, lisuride, A-372,159, Agomelatine, CPC, eltoprazine,

AL-38022A, CP-809,1 01 , etoperidone, fluoxetine, FR- fenfluramine, mesulergine, MK- 260,010, LU AA24530,

212, naphthyllisopropylamine, methysergide, nefazodone, norfenfluramine, ORG-12,962, norfluoxetine, O- ORG-37,684, oxaflozane, PNU- desmethyltramadol, RS-102,221 , 22395, PNU-181731 , SB-200,646, SB-221 ,284, SB- lysergamides, phenethylamines, 242,084, SDZ SER-082, piperazines, tryptamines, R06O- tramadol, and trazodone 0175, vabicaserin, WAY-629,

WAY-161 ,503, WAY-163,909,

and YM-348 Receptor Agonist Antagonist

-HT2A/2C Ketanserin, risperidone,

trazodone, mirtazapine, clozapine

-HT3 2-methyl-5-HT, alpha- Dolasetron, granisetron,

methyltryptamine, bufotenin, ondansetron, palonosetron, chlorophenylbiguanide, ethanol, tropisetron, alosetron, ibogaine, phenylbiguanide, cilanosetron, mirtazapine, AS- quipazine, RS-56812, SR-57227, 81 12, bantopride,

varenicline, and YM-31636 metroclopramide, renzapride, zacopride, mianserin, vortioxetine, clozapine, olanzapine, quetiapine, menthol, thujone, lamotigrine, and 3- tropanyl indole-3-carboxylate-HT4 Cisapride, tegaserod, Piboserod, GR-1 13,808, GR- prucalopride, BIMU-8, CJ- 125,487, RS-39604, SB-203,186, 033,466, ML-1 0302, mosapride, SB-204,070, and chamomile renzapride, RS-67506, RS- 67333, SL65.1055, zacopride,

metoclopramide, and sulpride

-HTSA Valeronic acid ASP-5736, AS-2030680, AS- 2674723, latrepiridine, risperidone, and SB-699,551-HTe EMDT, WAY-181 ,187, WAY- ALX-1 161 , AVN-21 1 , BVT-5182,

208,466, A/-(inden-5- BVT-7431 6, cerlapiridine, EGIS- yl)imidazothiazole-5-sulfonamide, 12233, idalopiridine, interpridine, E-6837, E-6801 , and EMD- latrepiridine, MS-245, PRX- 386,088 07034, SB-258,585, SB-271 ,046,

SB-357,134, SB-339,885, Ro 04- 6790, Ro-4368554, sertindole, olanzapine, asenapine, clozapine, rosa rugosa extract, and WAY-255315

-HT7 AS-1 9, 5-CT, 5-meot, 8-OH- Amisulpride, amitriptyline,

DAPT, aripiprazole, E-55888, E- amoxapine, clomipramine, 57431 , LP-12, LP-44, MSD-5a, clozapine, DR-4485,

RA-7, and N,N- fluphenazine, fluperlapine, ICI Dimethyltryptamine 169,369, imipramine,

ketanserine, JNJ-18038683, loxapine, lurasidone, LY- Receptor Agonist Antagonist

215,840, maprotiline, methysergide, mesulergine, mianserin, olanzepine, pimozide, ritanserin, SB-258,719, SB- 258,741 , SB-269,970, SB- 656,104-A, SB-691 ,673, sertindole, spiperone, tenilapine, TFMPP, vortioxetine, trifluoperazine, ziprasidone, and zotepine

Non-selective 5-HT antagonists Chlorpromazine, cyproheptadine, pizotifen, oxetorone, spiperone, ritanserin,

parachlorophenylalanine, metergoline, propranolol, mianserin, carbinoxamine, methdilazine, promethazine, pizotifen, oxatomide, feverfew, fenclonin, and reserpine

TABLE 2H: GLUATAMATE RECEPTOR AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist lonotropic (GRIA-14, GRI -5, AMPA, glutamic acid, ibotenic AP5, AP7, cppene, selfotel, HU- and GRIN1 -3B) acid, kainic acid, NMDA, 21 1 , Huperzine A, gabapentin, quisqualic acid remacemide, amantadine,

atomoxetine, AZD6765, agmatine, chloroform, dextrallorphan,

dextromethorphan, dextrorphan, diphenidine, dizocilpine (MK- 801 ), ethanol, eticyclidine, gacyclidine, ibogaine, ifenprodil, ketamine, kynurenic acid, memantine, magnesium, methoxetamine, nitromemantine, nitrous oxide, PD-137889, perampanel, phencyclidine, rolicyclidine, tenocyclidine, methoxydine, tiletamine, neramexane, eliprodil, etoxadrol, Receptor Agonist Antagonist

dexoxadrol, WMS-2539, N EFA, delucemine, 8A-PDHQ, aptiganel, rhynchophylline

Metabotropic (GRM1 -8) L-ap4, acpd, l-qa, chpg, ly- AIDA, fenobam, MPEP, LY- 379,268, ly-354,740, acpt, vu 367,385, EGLU, CPPG, MAP4, 01 55041 MSOP, LY-341 ,495

Glycine antagonists Rapastinel, NRX-1 074, 7- chlorokynurenic acid, 4- chlorokynurenine, 5,7- dichlorokynurenic acid, kynurenic acid, TK-40, 1 - aminocyclopropanecarboxylic acid (ACPC), L-phenylalanine, and xenon

TABLE 2I: HISTAMINE AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

doxylamine, ebastine, embramine, fexofenadine, fexofenadine hydrochloride, hydroxyzine, ketotifen fumarate, loratadine, meclizine, meclizine dihydrochloride, mepyramine maleate, mirtazapine, olopatadine, olopatadine hydrochloride, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, terfenadine, tripelennamine, zotepine, trans- triprolidine hydrochloride, and triprolidine

Hi inverse agonists Cetirizine, levocetirizine,

desloratadine, and pyrilamine

H ₂ Betazole, impromidine, dimaprit Aminopotentidine, cimetidine, dihydrochloride, and amthamine famotidine, ICI 162,846, dihyrdobromide lafutidine, nizatidine, ranitidine, ranitidine hyrdochloride, roxatidine, zolantadine dimaleate, and toitidine

H ₃ Imetit dihydropbromide, immepip Clobenpropit, clobenpropit

dihyrdrobromide, immethridine dihydrobromide, A 3314440 dihydrobromide, a- dihyrdochloride, BF 2649 Methylhistamine dihydrobromide, hydrochloride, carcinine

N-methylhistamine ditrifluoroacetate, ABT-239, dihydrochloride, proxyfan ciprofaxin, conessine, GT 2016, oxalate, and betahistine A-349,821 , impentamine

dihydrobromide, iodophenpropit dihydrobromide, JNJ 10181457 dihydrochloride, JNJ 5207852 dihydrochloride, ROS 234 dioxalate, SEN 12333, VUF 5681 dihydrobromide, and

thioperamide

H ₄ Imetit dihydropbromide, immepip Thioperamide, JNJ 7777120, A dihyrdrobromide, 4- 943931 dihydrochloride, A methylhistamine dihydrochloride, 987306, JNJ 1 0191584 maleate, Receptor Agonist Antagonist

clobenpropit dihydrobromide, and VUF-6002

VUF 10460, and VUF 8430

dihydrobromide

TABLE 2J: CANNABINOID AGONISTS AND ANTAGONISTS

Receptor Agonist Antagonist

Cannabinoid receptor (nonAnandamide, N-Arachidonoyl

selective) dopamine, 2-

Arachidonoylglycerol (2-AG), 2- Arachidonyl glyceryl ether, Δ-9- Tetrahydrocannabinol, EGCG,

Yangonin, AM-1221 , AM-1235,

AM-2232, UR-144, JWH-007,

JWH-015, JWH-018, ACEA,

ACPA, arvanil, CP 47497, DEA,

leelamine, methanandamide,

NADA, noladin ether, oleamide,

CB 65, GP-1 a, GP-2a, GW

405833, HU 308, JWH-133, L- 759,633, L-759,656, LEI 101 ,

MDA 19, and SER 601

CBi receptor ACEA, ACPA, RVD-Ηρα, (R)-(+)- Rimonabant, cannabidiol, Δ ⁹ - methanandamide tetrahydrocannabivarin (THCV), taranabant, otenabant, surinabant, rosonabant, SLV- 319, AVE1625, V24343, AM 251 , AM 281 , AM 6545, hemopressin, LY 320135, MJ 15, CP 945598, NIDA 41020, PF 514273, SLV 319, SR 1 141716A, and TC-C 14G

CB2 receptor CB 65, GP 1 a, GP 2a, GW Cannabidiol, Δ ⁹ - 405833, HU 308, JWH 133, L- tetrahydrocannabivarin (THCV), 759,656, L-759,633, SER 601 , AM 630, COR 170, JTE 907, and LEI 101 SR 144528

TABLE 2K: PURINERGIC RECEPTOR AGONISTS AND ANTAGONISTS Receptor Agonist Antagonist

ADORA1 (P1 adenosine Adenosine, N6- Caffeine, theophylline, 8- receptor) Cyclopentyladenosine, N6-3- Cyclopentyl-1 ,3-dimethylxanthine methoxyl-4-hydroxybenzyl (CPX), 8-Cyclopentyl-1 ,3- adenine riboside (B2), CCPA, dipropylxanthine (DPCPX), 8- tecadenoson, selodenoson, Phenyl-1 ,3-dipropylxanthine, Certain Benzodiazepines and bamifylline, BG-971 9, BG09928, Barbiturates, 2'-meccpa, GR FK-453, FK838, rolofylline, N- 79236, and SDZ WAG 994 0861 , and PSB 36

ADORA2A (P1 adenosine Adenosine, N6-3-methoxyl-4- Caffeine, theophylline, receptor) hydroxybenzyl adenine riboside istradefylline, SCH-58261 , SCH- (B2), YT-146, DPMA, UK- 442,416, ATL-444, MSX-3, 423,097, limonene, NECA, CV- preladenant, SCH-412,348, VER- 3146, binodenoson, ATL-146e, 6623, VER-6947, VER-7835, CGS-21680, and Regadenoson vipadenant, and ZM-241 ,385

ADORA2B (P1 adenosine Adenosine, 5'-N- Caffeine, theophylline, CVT- receptor) ethylcarboxamidoadenosine, 6883, ATL-801 , compound 38,

BAY 60-6583, LUF-5835, NECA, MRS-1 706, MRS-1754, OSIP- (S)-PHPNECA, and LUF-5845 339,391 , PSB-603, PSB-0788, and PSB-1 1 15

ADORA3 (P1 adenosine Adenosine, 2-(1 -Hexynyl)-N- Caffeine, theophylline, MRS- receptor) methyladenosine, CF-101 (IB- 1 191 , MRS-1220, MRS-1334,

MECA), CF-102, 2-CI-IB-MECA, MRS-1 523, MRS-3777,

CP-532,903, inosine, LUF-6000, MRE3008F20, MRE3005F20, and MRS-3558 OT-7999, SSR161421 , KF- 26777, PSB-10, PSB-1 1 , and VUF-5574

P2Y receptor ATP, ADP, UTP, UDP, UDP- Clopidogrel, elinogrel, prasugrel, glucose, 2-methylthioladenosine ticlopidine, ticagrelor, AR-C 5' diphosphate (2-mesadp), 1 18925XX, AR-C 66096, AR-C lysophosphatidic acid, PSB 1 1 14, 69931 , AZD 1283, MRS 21 79, PSB 0474, NF 546, MRS 2365, MRS 221 1 , MRS 2279, MRS MRS 2690, MRS 2693, MRS 2500, MRS 2578, NF 157, NF 2768, MRS 2905, MRS 2957, 340, PPADS, PPTN

MRS 4062, and denufosol (P2Y ₂ hydrochloride, PSD 0739, SAR agonist) 216471 , and suramin

P2X receptor Atp A 438079, A 740003, A 804598,

A 839977, AZ 10606120, AZ 1 1645373, 5-BDBD, BX 430, Evans Blue, JNJ 47965567, KN- 62, NF 023, NF 1 10, NF 157, NF Receptor Agonist Antagonist

279, NF 449, PPADS, iso- PPADS, PPNDS, Ro 0437626, Ro 51 , RO-3, TC-P 262, suramin, TNP-ATP, and P2X ₇ antagonists NF279, calmidazolium, and KN- 62

TABLE 2L: NEUROPEPTIDE AGONISTS AND ANTAGONISTS

Gene Agonist Antagonist

Neuropeptide Y receptor (nonNeuropeptide Y, pancreatic

selective) polypeptide, BWX-46, and

Peptide YY

Neuropeptide Yi receptor BVD-1 0, GR-231 ,1 18, BIBO- 3304, BIBP-3226, PD-160,170, and BMS 193885

Neuropeptide Y2 receptor BIIE-0246, CYM 9484, JNJ

5207787, and SF 1 1

Neuropeptide Y4 receptor UR-AK49 and GR-231 ,1 18

Neuropeptide Y5 receptor Lu AA-33810, CGP 71 683

hydrochloride, GW 438014A, L- 152,804, NPY 5RA972, NTNCB hydrochloride, velneperit, and S 25585

Somatostatin receptor Somatostatin, cortistatin, Cyclomastatin and CYN 154806 octreotide, lanreotide CH 275, TT

232, TC-G 1003, seglitide, RC

160, NNC 26-9100, L-817,818, L- 803,087 trifluoroacetate, and

(1 R,1 'S,3'R/1 R,VR,3'S)-L- 054,264

CGRP receptor (calcitonin gene- A-CGRP, β-CGRP, calcitonin, Telcagepant, sumatriptan related peptide receptor) PHM 27, amylin, pramlintide, (decreases CGRP promoter

CRSP-1 , and SUN-B 81 55 activity), MK-3207, and BIBN

4096 BS, MK-0974

Tachykinin 1 receptor (NKi Substance P, GR-73632, and Aprepitant, Casopitant, receptor) C14TKL-1 Ezlopitant, Fosaprepitant,

Lanepitant, Maropitant,

Vestipitant, L-733,060, L- Gene Agonist Antagonist

741 ,671 , L-742,694, RP-67580, RPR-100,893, CP-96345, CP- 99994, GR-205,1 71 , TAK-637, FK 888, GR 82334, L-760,735, L- 732,138, L-733,060, SDZ NKT 343, Spantide 1 , SR 140333, and T-2328

Tachykinin 2 receptor (NK2 Neurokinin A and GR-64349 Ibodutant, saredutant, GR- receptor) 159,897, GR 94800, MDL

29,913, and MEN 1 1420, MEN- 10376

Tachykinin 3 receptor (NK3 Neurokinin B and senktide Fezolinetant, MLE-4901 , receptor) Osanetant, Talnetant, SB- 222,200, SSR 146977, and SB- 218,795

Vasoactive intestinal polypeptide VIP, PACAP, PACAP-38, VIP (6-28), [D-p-CI-Phe ⁶ , Leu ¹² ]- receptor 1 (VIPR1 /VPAC1 ) and PACAP-27, peptide histidine VIP, and AC-Tyr ¹ ,D-Phe ² ]GRF 1 - Vasoactive intestinal polypeptide isoleucineamide (PHI), peptide 29 amide

receptor 2 (VIPR2/VPAC2) histidine methionineamide

(PHM), peptide histidine valine

(PHV), and Bay 55-9837

Opioid receptor (non-selective) Dynorphins, enkephalins,

endorphins, endomorphins, and

nociceptin

μ-opioid receptor DAMAGO, endomorphin-1 , Naloxone, naltrexone,

endomorphin-2, fentanyl, nalmefene, diprenorphine, loperamide, meptazinol, nalorphine, nalorphine oxycodone, PL 01 7, sinomenine, dinicotinate, levallorphan, and buprenorphine (partial) samidorphan, nalodeine,

alvimopan, methylnaltrexone, naloxegol, 6p-naltrexol, axelopran, bevenopran, methylsamidorphan,

naldemedine, buprenorphine, dezocine, eptazocine, CTAP, CTOP, cyprodime, clocinnamox mesylate, naloxonazine, funaltrexamine, and cyprodamine

K-opioid receptor Alazocine, Bremazocine, 8- 5'-Acetamidinoethylnaltrindole, Gene Agonist Antagonist

Carboxamidocyclazocine, 5'-Guanidinonaltrindole, 6'-

Cyclazocine, Ketazocine, Guanidinonaltrindole,

Metazocine, Pentazocine, Amentoflavone, AT-076,

Phenazocine, Morphinans (e.g., Binaltorphimine, BU09059,

6'-Guanidinonaltrindole, Buprenorphine, CERC-501 ,

Butorphan, Butorphanol, Dezocine, DIPPA, jdtic, LY-

Cyclorphan, Diprenorphine, 255582, LY-2459989, LY-

Etorphine, Levallorphan, 2795050, Methylnaltrexone,

Levomethorphan, Levorphanol, ML190, ML350, MR-2266,

Morphine, Nalbuphine, Naloxone, Naltrexone,

Nalfurafine, Nalmefene, Noribogaine, Norbinaltorphimine,

Nalodeine, Nalorphine, Pawhuskin A, PF-4455242,

Norbuprenorphine, Quadazocine, RB-64, and

Norbuprenorphine-3-glucuronide, Zyklophin

Oxilorphan, Oxycodone,

Proxorphan, Samidorphan, and

Xorphanol), Arylacetamides (e.g.,

Asimadoline, BRL-52537,

Eluxadoline, Enadoline, GR-

89696, ICI-204,448, ICI-199,441 ,

LPK-26, MB-1 C-OH, Niravoline,

N-MPPP, Spiradoline, U-50,488,

U-54.494A, and U-69,593),

CR665, Difelikefalin (CR845),

Dynorphins (dynorphin A,

dynorphin B, big dynorphin),

Terpenoids (e.g., Collybolide,

Erinacine E, Mentholm RB-64,

Salvinorin A, and 2-

Methoxymethyl salvinorin B),

Apadoline, HS665, HZ-2,

Ibogaine, Ketamine, Noribogaine,

Pentazocine, Tifluadom, and

Nalfurafine

δ-opioid receptor Leu-enkephalin, Met-enkephalin, Buprenorphine, naltriben,

Deltorphins I and II, DADLE, AR- naltrindole, SDM25N, ICI-

M 100390, 7- 174,864, ICI-154,129, BNTX, and

Spiroindanyloxymorphone, N- benzylnatrindole

Phenethyl-14-ethoxymetopon,

ADL-5859, BU-48, SNC-80, Gene Agonist Antagonist

SNC-162, FIT, 6'-GTI, DPDPE,

BW373U86, DPI-221 , DPI-287,

DPI-3290, TAN-67, RWJ- 394674, Norbuprenorphine,

Cannabidiol,

Tetrahydrocannabinol,

Xorphanol, Mitragynine, and

Mitragynine pseudoindoxyl

NOP receptor (opioid) Orphanin, SCH-221510, NNC UFP-101 , Trap 101 , nocistatin,

63-0532, MCOPPB, and Ac- BAN ORL 24, J 1 13397, JTC RYYRWK-NH2 801 , and SB 6121 1 1

Oxytocin receptor Carbetocin, demoxytocin, lipo- Atosiban, barusiban, epelsiban, oxytocin-1 , merotocin, oxytocin, L-368,899, L-371 ,257, L-372- TC OT 39, and WAY-267,464 662, retosiban, SSR-126,768, and WAY- 162,720

Vasopressin receptor Vasopressin and desmopressin TC OT 39, OPC 21268, SR

49059, TASP 0390325, conivaptan, tolvaptan, mozavaptan, lixivaptan, satavaptan, relcovaptan, nelivaptan, demeclocycline, and lithium

TABLE 2M : NEUROTRANSMISSION MODULATORS

Type Modulators

inhibitors (SNDRIs) and serotonin-norepinephrine esketamine, duloxetine, ketamine, phencyclidine, reuptake inhibitors (SNRIs) tripelennamine, mepiprazole, amitifadine, AN788,

(increase adrengergic, dopamine, and serotonin ansofaxine, centanafadine, atomoxetine, neurotransmission) desvenlafaxine, milnacipran, levomilnacipran, dasotraline, Lu AA34893, Lu AA37096, NS-2360, tedatioxetine, tesofensine, bicifadine, BMS- 866,949, brasofensine, diclofensine, DOV-216,303, EXP-561 , liafensine, NS-2359, RG-71 66, SEP- 227,162, SEP-228,425, SEP-228,432, naphyrone, 3,3-Diphenylcyclobutanamine, 3,4- Dichlorotametraline, D-161 , desmethylsertraline, DMNPC, DOV-102,677, fezolamine,

GSK1360707F, indatraline, JNJ-7925476, JZ-IV- 10, JZAD-IV-22, LR-5182, methylnaphthidate, MI-4, PRC200-SS, PRC050, PRC025, SKF-83,959, TP1 , phenyltropanes (e.g., WF-23, dichloropane, and RTI-55), Ginkgo biloba extract, St John's Wort, hyperforin, adhyperforin, and uliginosin B

Dopamine reuptake inhibitors Dopamine reuptake inhbiitors (e.g., altropane, (increase dopamine neurotransmission) amfonelic acid, amineptine, BTCP, 3C-PEP, DBL- 583, difluoropine, GBR-12783, GBR-12935, GBR- 13069, GBR-13098, GYKI-52895, lometopane, methylphenidate, ethylphenidate, modafinil, armodafinil, RTI-229, vanoxerine, adrafinil, benztropine, bupropion, fluorenol, medifoxamine, metaphit, rimcazole, venlafaxine, Chaenomeles speciosa, and oroxylin A), dopamine releasing agents (e.g., p-Tyramine), dextroamphetamine, lisdexamfetamine, dexmethylphenidate, and cathinone

Dopamine prodrugs Levopoda, docarpamine

(increase dopamine neurotransmission)

GABA reuptake inhibitors CL-996, deramciclane, gabaculine, guvacine, (increase GABA neurotransmission) nipecotic acid, NNC-71 1 , NNC 05-2090, SKF- 89976A, SNAP-51 14, tiagabine, and hyperforin

GABA analogs Gabapentin, butyric acid, valproic acid, valpromide,

(increase GABA neurotransmission) valnoctamide, 3-hydroxybutanal, GHB, sodium, oxybate, aceburic acid, GBL, GHBAL, GHV, GVL, GHC, GCL, HOCPCA, UMB68, pregabalin, tolibut, phaclofen, sacolfen, arecaidine, gaboxadol, Type Modulators

isonipecotic acid, 3-Methyl-GABA, AABA, BABA, DAVA, GAVA, Glutamic acid, hopantenic acid, piracetam, and vigabatrin

GABA prodrugs L-Glutamine, N-lsonicotinoyl-GABA, picamilon,

(increase GABA neurotransmission) progabide, tolgabide

Acetylcholinesterase inhibitors Carbamates, physostigmine, neostigmine, (increase nicotinic and muscarinic pyridostigmine, ambenonium, demecarium, neurotransmission) rivastigmine, phenanthrene derivatives,

galantamine, caffeine, rosmarinic acid, alpha- pinene, piperidines, donepezil, tacrine, edrophonium, Huperzine A, ladostigil, ungeremine, lactucopicrin, dyflos, echothiophate, parathion, and quasi-irreversible acetylcholinesterase inhibitors

Serotonin reuptake inhibitors Alaproclate, cericlamine, citalopram, dapoxetine, (increase serotonin neurotransmission) escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, RTI-353, sertraline, zimelidine, desmethylcitalopram,

didesmethylcitalopram, seproxetine ((S)- norfluoxetine), desvenlafaxine, cianopramine, litoxetine, lubazodone, SB-649,915, trazodone, vilazodone, vortioxetine, dextromethorphan, dextropropoxyphene, dimenhydrinate,

diphenhydramine, mepyramine (pyrilamine), mifepristone, delucemine, mesembrenone, mesembrine, roxindole, duloxetine,

levomilnacipran, milnacipran, dapoxetine, sibutramine, chlorpheniramine,

dextropmethorphan, and methadone

Serotonin releasing agents Chlorphentermine, cloforex, dexfenfluramine,

(increase serotonin neurotransmission) etolorex, fenfluramine, flucetorex, indeloxazine, levofenfluramine, tramadol, carbamazepine, amiflamine (FLA-336), viqualine (PK-5078), 2- Methyl-3,4-methylenedioxyamphetamine (2-Methyl- MDA), 3-Methoxy-4-methylamphetamine (MMA), 3- Methyl-4,5-methylenedioxyamphetamine (5-Methyl- MDA), 3,4-Ethylenedioxy-/V-methylamphetamine (EDMA), 4-Methoxyamphetamine (PMA), 4- Methoxy-/V-ethylamphetamine (PMEA), 4-Methoxy- /V-methylamphetamine (PMMA), 4- Type Modulators

Methylthioamphetamine (4-MTA), 5-(2- Aminopropyl)-2,3-dihydrobenzofuran (5-APDB), 5- lndanyl-2-aminopropane (IAP), 5-Methoxy-6- methylaminoindane (MMAI), 5-Trifluoromethyl-2- aminoindane (TAI), 5,6-Methylenedioxy-2- aminoindane (MDAI), 5,6-Methylenedioxy-/V- methyl-2-aminoindane (MDMAI), 6-Chloro-2- aminotetralin (6-CAT), 6-Tetralinyl-2-aminopropane (TAP), 6,7-Methylenedioxy-2-aminotetralin (MDAT), 6,7-Methylenedioxy-N-methyl-2-aminotetralin (MDMAT), A/-Ethyl-5-trifluoromethyl-2-aminoindane (ETAI), A/-Methyl-5-indanyl-2-aminopropane, aminorex, MDMA, MDEA, MDA, MBDB, and tryptamines, such as DMT, amt, 5meo-NMT, NMT, NETP, Dimethyl-Serotonin, 5meo-NET, aet and amt

Excitatory amino acid reuptake inhibitors Didydrokanic acid, WAY-213,613, L-trans-2,4-PDC, (increase Glutamate receptor neurotransmission) amphetamine, and L-Theanine

Glycine reuptake inhibitors Bitopertin, Org 24598, Org 25935, ALX-5407,

(increase Glutamate receptor neurotransmission) sacrosine, Org 25543, and N-arachidonylglycerine

Histidine decarboxylase inhibitors Tritoqualine, catechin

(decrease histamine neurotransmission)

Endocannabinoid enhancers AM404, fatty acid amide hydrolase inhibitors (e.g.,

(increase cannabinoid neurotransmission) AM374, ARN2508, BIA 10-2472, BMS-469908,

CAY-1 0402, JNJ-245, JNJ-1661010, JNJ- 28833155, JNJ-40413269, JNJ-421 19779, JNJ- 42165279, MK-3168, MK-4409, MM-433593, OL- 92, OL-135, PF-622, PF-750, PF-3845, PF- 04457845, PF-04862853, RN-450, SA-47, SA-73, SSR-41 1298, ST-4068, TK-25, URB524, URB597, URB694, URB937, VER-156084, and V-158866

Monoacylglycerol lipase inhibitors /V-arachidonoyl maleimide, JZL184

(increase cannabinoid neurotransmission)

Endocannabinoid transporter inhibitors Sb-fi-26

(increase cannabinoid neurotransmission)

Endocannabinoid reuptake inhibitors AM404, AM1 172, LY-21 83240, O-2093, OMDM-2, (increase cannabinoid neurotransmission) UCM-707, VDM-1 1 , guineensine, ETI-T-24_B_I,

WOBE437, and RX-055

Adenosine uptake inhibitors Cilostazol, dilazep, and dipyramidole Type Modulators

(increase purinergic neurotransmission)

Nucleoside transporter inhibitors 8MDP, Decynium 22, 5-iodotubercidin, NBMPR, (increase purinergic neurotransmission) and TC-T 6000

Neurotoxins

In some embodiments, the neurotransmission modulator is a neurotoxin (e.g., a neurotoxin listed in Table 3), or a functional fragment or variant thereof. Neurotoxins include, without limitation, convulsants, nerve agents, parasympathomimetics, and uranyl compounds. Neurotoxins may be bacterial in origin, or fungal in origin, or plant in origin, or derived from a venom or other natural product. Neurotoxins may be synthetic or engineered molecules, derived de novo or from a natural product. Suitable neurotoxins include but are not limited to botulinum toxin and conotoxin. Exemplary neurotoxins are listed in Table 3.

TABLE 3: NEUROTOXINS

NEUROTOXINS

2,4,5-Trihydroxyamphetamine

2,4,5-Trihydroxymethamphetamine

3,4-Dichloroamphetamine

5,7-Dihydroxytryptamine

5-lodowillardiine

Ablomin

Aconitine

Aconitum

Aconitum anthora

AETX

Agelenin

Agitoxin

Aldrin

Alpha-Methyldopamine

Alpha-neurotoxin

Altitoxin

Anatoxin-a

Androctonus australis hector insect

toxin

Anisatin

Anthopleurin

Antillatoxin

Anuroctoxin

Apamin NEUROTOXINS

Delta atracotoxin

Dendrotoxin

Dieldrin

Diisopropyl fluorophosphates

Dimethylmercury

Discrepin

Domoic acid

Dortoxin

DSP-4

Ergtoxin

Falcarinol

Fenpropathrin

Gabaculine

Ginkgotoxin

Grammotoxin

Grayanotoxin

Hainantoxin

Halcurin

Hefutoxin

Helothermine

Heteroscodratoxin-1

Histrionicotoxin

Homoquinolinic acid

Hongotoxin

Huwentoxin

Ibotenic acid

Ikitoxin

Inhibitor cystine knot

Jingzhaotoxin

Kainic acid

Kaliseptine

Kappa-bungarotoxin

Kodaikanal mercury poisoning

Kurtoxin

Latrotoxin

Lq2

Maitotoxin

Margatoxin

Maurotoxin NEUROTOXINS

Mercury (element)

Methanol

Methiocarb

MPP+

MPTP

Nemertelline

Neosaxitoxin

Nicotine

N-Methylconiine

Oenanthotoxin

Oxalyldiaminopropionic acid

Oxidopamine

Oxotoxin

Pahutoxin

Palytoxin

Pandinotoxin

Para-Bromoamphetamine

Para-Chloroamphetamine

Para-Chloromethamphetamine

Para-lodoamphetamine

Penitrem A

Phaiodotoxin

Phenol

Phoneutria nigriventer toxin-3

Phrixotoxin

Polyacrylamide

Poneratoxin

Psalmotoxin

Pumiliotoxin

Quinolinic acid

Raventoxin

Resiniferatoxin

Samandarin

Saxitoxin

Scyllatoxin

Sea anemone neurotoxin Slotoxin

SNX-482

Stichodactyla toxin NEUROTOXINS

Taicatoxin

Taipoxin

Tamapin

Tertiapin

Tetanospasmin

Tetraethylammonium

Tetramethylenedisulfotetramine

Tetrodotoxin

Tityustoxin

Tricresyl phosphate

TslV

Vanillotoxin

Veratridine

Neurotransmission modulators also include antibodies that bind to neurotransmitters or neurotransmitter receptors listed in Tables 1 A, 1 B, Table 7, and Table 8 and decrease neurotransmission. These antibodies include blocking and neutralizing antibodies. Antibodies to neurotransmitters or neurotransmitter receptors listed in Tables 1 A, 1 B, Table 7, and Table 8 can be generated by those of skill in the art using well established and routine methods.

Neuropeptide signaling modulators

In some embodiments, a neuromodulating agent is a neuropeptide signaling modulator (e.g., an agent that increases or decreases neuropeptide signaling), such as a blocker or agonist of a

neuropeptide receptor listed in Table 1 A. Neuromodulating agents that increase neuropeptide signaling include neuropeptides and neuropeptide receptors (e.g., a neuropeptide (ligand) listed in Table 1 A, Table 1 B, or Table 7, e.g., a neuropeptide having the sequence referenced by accession number or Entrez Gene ID of a neuropeptide listed in Table 1 A, Table 1 B, or Table 7, or an analog thereof, e.g., a sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity to the sequence referenced by accession number or Entrez Gene ID. The neuromodulating agent can be an

endocannabinoid, amine, amino acid, purine, gas, gastrin, opioid, monoamine, secretin, tachykinin, neuropeptide, neurohypophyseal, orexin, or somatostatin, e.g., listed in Table 1 B. In some embodiments, neuropeptide signaling is increased by administering, locally delivering, or stabilizing a neuropeptide listed in Tables 1 A, 1 B, or encoded by a gene in Table 7. Neuromodulating agents that increase neuropeptide signaling also include agents that increase neuropeptide receptor activity (e.g.,

neuromodulating agents that increase the activity of a neuropeptide receptor or signaling protein listed in Table 1 A or encoded by a gene in Table 7 via upregulation, stabilization, agonism, or overexpression). Exemplary neuropeptide agonists are listed in Table 2A and 2L. Neuromodulating agents that increase neuropeptide signaling also include agents that reduce neuropeptide degradation or reuptake, agents that increase neuropeptide synthesis or release (e.g., agents that increase the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via stabilization, overexpression, or upregulation), increase neuropeptide receptor synthesis or membrane insertion, and regulate neuropeptide receptor conformation (e.g., agents that bind to a receptor and keep it in an "open" or "primed" conformation). Neuropeptide signaling modulators can increase neuropeptide signaling by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.

Neuromodulating agents that decrease neuropeptide signaling include agents that decrease neuropeptide receptor activity (e.g., neuromodulating agents that decrease the activity of a neuropeptide receptor or signaling protein listed in Table 1 A or encoded by a gene in Table 7 via blockade, antagonism, or downregulation). Exemplary neuropeptide antagonists are listed in Table 2A or 2L. Neuromodulating agents that decrease neuropeptide signaling also include agents that bind to neuropeptides or block their interaction with receptors (e.g., neuropeptide blocking or neutralizing antibodies), agents that increase neuropeptide degradation or clearance, agents that decrease neuropeptide synthesis or release (e.g., agents that decrease the activity of a biosynthetic protein encoded by a gene in Table 1 A or Table 7 via inhibition or downregulation), decrease neuropeptide receptor synthesis or membrane insertion, and regulate neuropeptide receptor conformation (e.g., agents that bind to a receptor and keep it in a "closed" or "inactive" conformation). In some embodiments, neuropeptide signaling is decreased by sequestering, blocking, antagonizing, or degrading a

neuropeptide listed in Tables 1 A, 1 B, or encoded by a gene in Table 7. Neuropeptide signaling modulators can decrease neuropeptide signaling by 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or more.

Neuropeptide signaling modulators also include antibodies that bind to neuropeptides or neuropeptide receptors listed in Tables 1 A, 1 B, and Table 7 and decrease neuropeptide signaling. These antibodies include blocking and neutralizing antibodies. Exemplary neuropeptide signaling blocking and neutralizing antibodies are listed below in Table 4. Antibodies to neuropeptides and neuropeptide receptors listed in Tables 1 A, 1 B, and Table 7 can also be generated by those of skill in the art using well established and routine methods.

TABLE 4: NEUROPEPTIDE AND NEUROPEPTIDE RECEPTOR ANTIBODIES

Neuronal growth factor modulators

In some embodiments, a neuromodulating agent is a neuronal growth factor modulator (e.g., an agent that decreases or increases neurogenic/axonogenic signals, e.g., a neuronal growth factor or neuronal growth factor mimic, or an agonist or antagonist of a neuronal growth factor or neuronal growth factor receptor). For example, the neuromodulating agent is a neuronal growth factor listed in Table 1 C or Table 7, e.g., a neuronal growth factor having the sequence referenced by accession number or Entrez Gene ID in Table 1 C or Table 7, or an analog thereof, e.g., a sequence having at least 75%, 80%, 85%, 90%, 90%, 98%, 99% identity to the sequence referenced by accession number or Entrez Gene ID in Table 1 C or Table 7. Neuronal growth factor modulators also include agonists and antagonists of neuronal growth factors and neuronal growth factor receptors listed in Table 1 C or Table 7. A neuronal growth factor modulator may increase or decrease neurogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization. Neuronal growth factor modulators regulate innervation and the formation of synaptic connections between two or more neurons and between neurons and non-neural cells. A neuronal growth factor modulator may block one or more of these processes (e.g., through the use of antibodies that block neuronal growth factors or their receptors) or promote one or more of these processes (e.g., through the use of neuronal growth factors or analogs thereof). Neuronal growth factor modulators can increase or decrease one of the above mentioned processes by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 200%, 500% or more.

In some embodiments, the neuromodulating agent decreases neurogenic/axonogenic signals, e.g., the method includes administering to the subject or contacting a cell with a neuromodulating agent (e.g., a neuronal growth factor modulator) in an amount and for a time sufficient to decrease

neurogenesis or axonogenesis. For example, the neuromodulating agent that leads to a decrease in neurogenesis or axonogenesis is a blocking or neutralizing antibody against a neurotrophic factor.

Relevant neurotrophic factors include NGF, BDNF, ProNGF, Sortilin, TGFp and TGFp family ligands and receptors (e.g., TGFpRI , TGFpR2, TGFpl , TGFp2 TGFp4), GFRa family ligands and receptors (e.g., GFRal , GFRa2, GFRa3, GFRa4, GDNF), CNTF, LIF, neurturin, artemin, persephin, neurotrophin, chemokines, cytokines, and others listed in Table 1 C or Table 7. Receptors for these factors can also be targeted, as well as downstream signaling pathways including Jak-Stat inducers, and cell cycle and MAPK signaling pathways. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by sequestering, blocking, antagonizing, degrading, or downregulating a neuronal growth factor or a neuronal growth factor receptor listed in Table 1 C or encoded by a gene in Table 7. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by blocking or antagonizing a signaling protein encoded by a gene in Table 7 that is downstream of a neuronal growth factor. In some embodiments, the neuronal growth factor modulator decreases neurogenesis, axonogenesis or any of the processes mentioned above by blocking, disrupting, or antagonizing a synaptic or structural protein encoded by a gene in Table 7. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be decreased in the subject at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be decreased in the subject between 5-20%, between 5-50%, between 1 0-50%, between 20-80%, between 20-70%.

In some embodiments, the neuromodulating agent is one that increases neurogenic/axonogenic signals, e.g., the method includes administering to the subject or contacting a cell with a neuromodulating agent (e.g., a neuronal growth factor modulator) in an amount and for a time sufficient to increase neurogenesis or axonogenesis. For example, the neuromodulating agent that leads to an increase in neurogenesis or axonogenesis is a neurotrophic factor. Relevant neurotrophic factors include NGF, BDNF, ProNGF, Sortilin, TGFp and TGFp family ligands and receptors (e.g., TGFpRI , TGFpR2, TGFpl , TGFp2 TGFp4), GFRa family ligands and receptors (e.g., GFRal , GFRa2, GFRa3, GFRa4, GDNF), CNTF, LIF, neurturin, artemin, persephin, neurotrophin, chemokines, cytokines, and others listed in Table 1 C or Table 7. Receptors for these factors may also be targeted, as well as downstream signaling pathways including Jak-Stat inducers, and cell cycle and MAPK signaling pathways. In some embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by administering, locally delivering, or stabilizing a neuronal growth factor listed in Table 1 C or encoded by a gene in Table 7, or by upregulating, agonizing, or stabilizing a neuronal growth factor receptor listed in Table 1 C or encoded by a gene in Table 7. In some

embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by stabilizing, agonizing, overexpressing, or upregulating a signaling protein encoded by a gene in Table 7 that is downstream of a neuronal growth factor. In some embodiments, the neuronal growth factor modulator increases neurogenesis, axonogenesis or any of the processes mentioned above by stabilizing, overexpressing, or upregulating a synaptic or structural protein encoded by a gene in Table 7. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be increased in the subject at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. Neurogenesis, axonogenesis, neuronal growth, neuronal differentiation, neurite outgrowth, synapse formation, synaptic maturation, synaptic refinement, or synaptic stabilization can be increased in the subject between 5-20%, between 5-50%, between 10- 50%, between 20-80%, or between 20-70%.

In some embodiments, the neuromodulating agent that increases or decreases the number of nerves in an affected tissue. For example, the subject has cancer (e.g., the subject has a highly innervated tumor). For example, the neuromodulating agent is administered in an amount and for a time sufficient to decrease neurogenesis/axonogenesis. The neuromodulating agent can be, e.g., an inhibitor of neuronal growth factor signaling such as a blocking antibody directed to a neuronal growth factor or neuronal growth factor receptor.

Neuronal growth factor modulators also include antibodies that bind to neuronal growth factors or neuronal growth factor receptors and decrease their signaling (e.g., blocking antibodies). Exemplary neuronal growth factor blocking antibodies are listed below in Table 5. Antibodies to neuronal growth factors listed in Table 1 C and Table 7 can also be generated by those of skill in the art using well established and routine methods.

TABLE 5: NEURONAL GROWTH FACTOR ANTIBODIES

Neuronal Growth Factor Antibody Company

BDNF 38B8 (agonist antibody) Pfizer

BDNF 29D7 (agonist antibody) Pfizer

EphA3 KB004 KaloBios Pharmaceuticals, Inc.

IFNA1 Faralimomab Creative Biolabs Neuronal Growth Factor Antibody Company

IFNA1 Sifalimumab (MEDI-545) Medlmmune

IFNA1 Rontalizumab Genentech

IGF Figitumumab (CP-751 ,871 ) - an Pfizer

IGR-1 R MAb

IGF SCH717454 (Robatumamab, Merck

inhibits IGF initiated

phosphorylation)

IGF Cixutumumab (IGF-1 R antibody) Eli Lilly

IGF Teprotumumab (IGF-1 R Genmab/Roche

blocking antibody)

IGF-2 Dusigitumab Med I m m u n e/Ast raZe n eca

IGF-2 DX-2647 Dyax/Shire

IGF Xentuzumab Boehringer Ingelheim/Eli Lilly

IGF Dalotuzumab (IGFR1 blocking Merck & Co.

antibody)

IGF Figitumumab (IGFR1 blocking Pfizer

antibody)

IGF Ganitumab (IGFR1 blocking Amgen

antibody)

IGF Robatumumab (IGFR1 blocking Roche/Schering-Plough antibody)

IL1 B Canakinumab Novartis

IL1 B APX002 Apexigen

IL1 B Gevokizumab XOMA

IL4 Pascolizumab GlaxoSmithKline

IL4 Dupilumab Regeneraon/Sanofi

IL6 Siltuximab Janssen Biotech, Inc.

IL6 Olokizumab UCB/R-Pharm

IL6 Elsilimomab Orphan Pharma International

IL6 Sirukumab Centocor

IL6 Clazakizumab Bristol Myers Squib/Alder

Biopharmaceuticals

IL6 Gerilimzumab (ARGX-109) arGEN-X/RuiYi

IL6 FE301 Ferring Pharmaceuticals

IL6 FM101 Femta Pharmaceuticals

IL-6R Sarilumab (directed against Regeneron/Sanofi

IL6R)

IL-6R Tocilizumab Hoffmann-La Roche/Chugai

IL-6R Sapelizumab Chugai Neuronal Growth Factor Antibody Company

IL-6R Vobarilizumab Ablynx

L1 CAM AB417 Creative biolabs

L1 CAM L1 -9.3 Creative biolabs

L1 CAM L1 -14.10 Biolegend

NGF Tanezumab Pfizer

NGF Fulranumab (JNJ-42160443), Amgen

NGF MNAC13 (anti-TrkA, the NGF Creative Biolabs

receptor)

NGF mAb 91 1 Rinat/Pfizer

NGF Fasinumab Regeneron/Teva

NRG1 538.24 Hoffman-La Roche

NRP1 Vesencumab Genentech/Roche

ROR1 Cirmtuzumab Oncternal Therapeutics

SAP GSK2398852 GlaxoSmithKline

TGFp Fresolimumab (pan-TGFp Genzyme/Aventis

antibody)

TGFp IMC-TR1 (LY3022859) (MAb Eli Lilly

against TGFpRII)

TGFp TpM1 (anti-TGFpl MAb) Eli Lilly

TGFp2 Lerdelimumab (CAT-152) Genzyme

TGFpl Metelimumab Genzyme

TGFpl LY2382770 Eli Lilly

TGFp PF-03446962 (MAb against Pfizer

TGFpRI)

TNF Infliximab Janssen Biotech, Inc.

TNF Adalimumab Abb Vie Inc.

TNF Certolizumab pegol UCB

TNF Golimumab Janssen Biotech, Inc.

TNF Afelimomab

TNF Placulumab Teva Pharmaceutical Industries,

Inc.

TNF Nerelimomab Chiron/Celltech

TNF Ozoralizumab Pfizer/Ablynx

VEGFA Bevacizumab Genzyme

VEGFA Ranibizumab Lucentis

VEGF Alacizumab pegol (anti- UCB

VEGFR2)

VEGFA Brolucizumab Novartis

VEGF lcrucumab (anti-VEGFR1 ) Eli Lilly Neuronal Growth Factor Antibody Company

VEGF Ramucirumab (anti-VEGFR2) Eli Lilly

Neuronal growth factor modulators also include agents that agonize or antagonize neuronal growth factors and neuronal growth factor receptors. For example, neuronal growth factor modulators include TNF inhibitors (e.g., etanercept, thalidomide, lenalidomide, pomalidomide, pentoxifylline, bupropion, and DOI), TGFpl inhibitors, (e.g., disitertide (P144)), TGFp2 inhibitors (e.g., trabedersen (AP12009)). Exemplary neuronal growth factor agonists and antagonists are listed in Table 6.

TABLE 6: NEURONAL GROWTH FACTOR AGONISTS AND ANTAGONISTS

Modulators of gene expression

In some embodiments, a neuromodulating agent is a neurome gene expression modulator (e.g., an agent that affects the expression of a neurome gene listed in Table 7 or Table 8, e.g., a channel, transporter, neuropeptide, neurotransmitter, neurotrophic, signaling, synaptic, biosynthesis, ligand, receptor, structural, or vesicular gene). A neurome gene expression modulator can affect gene expression through modulation of gene transcription, gene translation, or protein levels. Neurome gene expression modulators may increase gene expression through epigenetic modifications (e.g., demethylation or acetylation), post-translational modifications (e.g., reducing ubiquitination, or altering sumoylation or phosphorylation), by increasing mRNA translation and stability, or through delivery of exogenous genetic material (e.g., a viral vector expressing a gene of interest). In some embodiments, the neurome gene expression modulator increases neurome gene expression by stabilizing, upregulating, or promoting overexpression of a biosynthesis, channel, ligand, receptor, signaling, structural, synaptic, transporter, vesicular, neuropeptide, neurotransmitter, or neurotrophic gene in Table 7 or a channel or transporter gene in Table 8. Neurome gene expression modulators may decrease gene expression through epigenetic modifications (e.g., methylation or deacetylation), post-translational modifications (e.g., increasing ubiquitination, or altering sumoylation or phosphorylation), or by decreasing mRNA translation and stability (e.g., using miRNA, siRNA, shRNA, or other therapeutic RNAs). In some embodiments, the neurome gene expression modulator decreases neurome gene expression by downregulating, inhibiting, or disrupting expression of a biosynthesis, channel, ligand, receptor, signaling, structural, synaptic, transporter, vesicular, neuropeptide, neurotransmitter, or neurotrophic gene in Table 7 or a channel or transporter gene in Table 8. A neurome gene expression modulator may increase or decrease gene expression by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or more.

In some embodiments, a neurome gene expression modulator increases or decreases the expression of a neurome gene listed in Table 7 to treat a subject with cancer (e.g., a cancer that expresses the neurome gene, e.g., through altering the growth, metastasis, invasion, proliferation, or viability of the cancer cell expressing the modulated gene). In some embodiments, a neurome gene expression modulator increases or decreases the expression of a neurome gene listed in Table 1 0 or in Table 12, 13, or 14A-14C to treat the corresponding cancer. The neurome gene expression modulator can be introduced systemically (e.g., injected intravenously into blood stream), or administered locally (e.g., administered to a tumor or a tissue at risk of developing a tumor).

Table 7: NEUROME GENES

Approved Approved name Entrez Gene type / Category Symbol Gene ID family

ABAT 4-aminobutyrate 18 Neurotransmitter Biosynthesis

aminotransferase

ACHE Acetylcholinesterase 43 Neurotransmitter Biosynthesis

ACTR1 A ARP1 actin-related protein 1 10121 Synaptic Structural Approved Approved name Entrez Gene type / Category Symbol Gene ID family

homolog A, centractin alpha

ACTR1 B ARP1 actin-related protein 1 10120 Synaptic Structural homolog B, centractin beta

ADCY1 Adenylate cyclase 1 107 Signaling Signaling

ADCY10 Adenylate cyclase 10, soluble 5581 1 Signaling Signaling

ADCY2 Adenylate cyclase 2 108 Signaling Signaling

ADCY3 Adenylate cyclase 3 109 Signaling Signaling

ADCY4 Adenylate cyclase 4 196883 Signaling Signaling

ADCY5 Adenylate cyclase 5 1 1 1 Signaling Signaling

ADCY6 Adenylate cyclase 6 1 12 Signaling Signaling

ADCY7 Adenylate cyclase 7 1 13 Signaling Signaling

ADCY8 Adenylate cyclase 8 1 14 Signaling Signaling

ADCY9 Adenylate cyclase 9 1 15 Signaling Signaling

ADCYAP1 Adenylate cyclase activating 1 16 Signaling Signaling polypeptide 1

ADCYAP1 R ADCYAP receptor type I 1 17 Neurotransmitter Receptor 1

ADIPOQ Adiponectin, C1 Q and 9370 Neuropeptide Ligand collagen domain containing

ADK Adenosine kinase 132 Signaling Signaling

ADM Adrenomedullin 133 Neuropeptide Ligand

ADM2 Adrenomedullin 2 79924 Neuropeptide Ligand

ADNP Activity dependent 23394 Signaling Structural neuroprotector homeobox

ADORA2A Adenosine A2a receptor 135 Neurotransmitter Receptor

ADORA2B Adenosine A2b receptor 136 Neurotransmitter Receptor

ADRA1 A Adrenoceptor alpha 1 A 148 Neurotransmitter Receptor

ADRA1 B Adrenoceptor alpha 1 B 147 Neurotransmitter Receptor

ADRA1 D Adrenoceptor alpha 1 D 146 Neurotransmitter Receptor

ADRA2A Adrenoceptor alpha 2A 150 Neurotransmitter Receptor

ADRA2B Adrenoceptor alpha 2B 151 Neurotransmitter Receptor

ADRA2C Adrenoceptor alpha 2C 152 Neurotransmitter Receptor

ADRB1 Adrenoceptor beta 1 153 Neurotransmitter Receptor

ADRB2 Adrenoceptor beta 2 154 Neurotransmitter Receptor

ADRB3 Adrenoceptor beta 3 155 Neurotransmitter Receptor

AGRN Agrin 375790 Neuropeptide Ligand

AGRP Agouti related neuropeptide 181 Neuropeptide Ligand

AGT Angiotensinogen 183 Neuropeptide Ligand Approved Approved name Entrez Gene type / Category Symbol Gene ID family

AGTR1 Angiotensin II receptor type 1 185 Neuropeptide Receptor

AKAP1 A-kinase anchoring protein 1 8165 Signaling Signaling

AKAP10 A-kinase anchoring protein 10 1 121 6 Signaling Signaling

AKAP1 1 A-kinase anchoring protein 1 1 1 121 5 Signaling Signaling

AKAP12 A-kinase anchoring protein 12 9590 Signaling Signaling

AKAP13 A-kinase anchoring protein 13 1 1214 Signaling Signaling

AKAP14 A-kinase anchoring protein 14 158798 Signaling Signaling

AKAP17A A-kinase anchoring protein 8227 Signaling Signaling

17A

AKAP2 A-kinase anchoring protein 2 1 121 7 Signaling Signaling

AKAP3 A-kinase anchoring protein 3 10566 Signaling Signaling

AKAP4 A-kinase anchoring protein 4 8852 Signaling Signaling

AKAP5 A-kinase anchoring protein 5 9495 Signaling Signaling

AKAP6 A-kinase anchoring protein 6 9472 Signaling Signaling

AKAP7 A-kinase anchoring protein 7 9465 Signaling Signaling

AKAP8 A-kinase anchoring protein 8 10270 Signaling Signaling

AKAP9 A-kinase anchoring protein 9 10142 Signaling Signaling

AKT1 AKT serine/threonine kinase 1 207 Signaling Signaling

AKT2 AKT serine/threonine kinase 2 208 Signaling Signaling

AKT3 AKT serine/threonine kinase 3 10000 Signaling Signaling

ALDH5A1 Aldehyde dehydrogenase 5 7915 Other Miscelaneous family member A1

ALDH9A1 Aldehyde dehydrogenase 9 223 Other Miscelaneous family member A1

ALOX15 Arachidonate 15-lipoxygenase 246 Other Miscelaneous

ALPL Alkaline phosphatase, 249 Other Miscelaneous liver/bone/kidney

ANXA1 Annexin A1 301 Other Miscelaneous

AP3B2 Adaptor related protein 8120 Vesicular Vesicles complex 3 beta 2 subunit

AP3D1 Adaptor related protein 8943 Vesicular Vesicles complex 3 delta 1 subunit

APLN Apelin 8862 Neuropeptide Ligand

APOE Apolipoprotein E 348 Other Miscelaneous

ARID1 B AT-rich interaction domain 1 B 57492 Other Miscelaneous

ARPP1 9 Camp regulated 10776 Signaling Signaling phosphoprotein 19

ARR3 Arrestin 3 407 Signaling Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

ARRB1 Arrestin beta 1 408 Signaling Signaling

ARRB2 Arrestin beta 2 409 Signaling Signaling

ARTN Artemin 9048 Neurotrophic Ligand

ASIC1 Acid sensing ion channel 41 Channel or Channel subunit 1 transporter

ASIC2 Acid sensing ion channel 40 Channel or Channel subunit 2 transporter

ASIC3 Acid sensing ion channel 931 1 Channel or Channel subunit 3 transporter

ASIP Agouti signaling protein 434 Neuropeptide Ligand

ATP1 OA Atpase phospholipid 57194 Channel or Transporter transporting 10A (putative) transporter

ATP10B Atpase phospholipid 23120 Channel or Transporter transporting 10B (putative) transporter

ATP10D Atpase phospholipid 57205 Channel or Transporter transporting 10D (putative) transporter

ATP1 1 A Atpase phospholipid 23250 Channel or Transporter transporting 1 1 A transporter

ATP1 1 B Atpase phospholipid 23200 Channel or Transporter transporting 1 1 B (putative) transporter

ATP1 1 C Atpase phospholipid 286410 Channel or Transporter transporting 1 1 C transporter

ATP12A Atpase H+/K+ transporting 479 Channel or Transporter non-gastric alpha2 subunit transporter

ATP1 A1 Atpase Na+/K+ transporting 476 Channel or Transporter subunit alpha 1 transporter

ATP1 A2 Atpase Na+/K+ transporting 477 Channel or Transporter subunit alpha 2 transporter

ATP1 A3 Atpase Na+/K+ transporting 478 Channel or Transporter subunit alpha 3 transporter

ATP1 A4 Atpase Na+/K+ transporting 480 Channel or Transporter subunit alpha 4 transporter

ATP1 B1 Atpase Na+/K+ transporting 481 Channel or Transporter subunit beta 1 transporter

ATP1 B2 Atpase Na+/K+ transporting 482 Channel or Transporter subunit beta 2 transporter

ATP1 B3 Atpase Na+/K+ transporting 483 Channel or Transporter subunit beta 3 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

ATP2A1 Atpase 487 Channel or Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting 1

ATP2A2 Atpase 488 Channel or Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting 2

ATP2A3 Atpase 489 Channel or Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting 3

ATP2B1 Atpase plasma membrane 490 Channel or Transporter

Ca2+ transporting 1 transporter

ATP2B2 Atpase plasma membrane 491 Channel or Transporter

Ca2+ transporting 2 transporter

ATP2B3 Atpase plasma membrane 492 Channel or Transporter

Ca2+ transporting 3 transporter

ATP2B4 Atpase plasma membrane 493 Channel or Transporter

Ca2+ transporting 4 transporter

ATP2C1 Atpase secretory pathway 27032 Channel or Transporter

Ca2+ transporting 1 transporter

ATP2C2 Atpase secretory pathway 9914 Channel or Transporter

Ca2+ transporting 2 transporter

ATP4A Atpase H+/K+ transporting 495 Channel or Transporter alpha subunit transporter

ATP4B Atpase H+/K+ transporting 496 Channel or Transporter beta subunit transporter

ATP5A1 ATP synthase, H+ 498 Channel or Transporter transporting, mitochondrial F1 transporter

complex, alpha subunit 1 ,

cardiac muscle

ATP5B ATP synthase, H+ 506 Channel or Transporter transporting, mitochondrial F1 transporter

complex, beta polypeptide

ATP5C1 ATP synthase, H+ 509 Channel or Transporter transporting, mitochondrial F1 transporter

complex, gamma polypeptide

1

ATP5D ATP synthase, H+ 513 Channel or Transporter transporting, mitochondrial F1 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

complex, delta subunit

ATP5E ATP synthase, H+ 514 Channel or Transporter transporting, mitochondrial F1 transporter

complex, epsilon subunit

ATP5F1 ATP synthase, H+ 515 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit B1

ATP5H ATP synthase, H+ 10476 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit D

ATP5I ATP synthase, H+ 521 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit E

ATP5J ATP synthase, H+ 522 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit F6

ATP5J2 ATP synthase, H+ 9551 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit F2

ATP5L2 ATP synthase, H+ 267020 Channel or Transporter transporting, mitochondrial Fo transporter

complex subunit G2

ATP6V0A1 Atpase H+ transporting V0 535 Channel or Transporter subunit a1 transporter

ATP6V0A2 Atpase H+ transporting V0 23545 Channel or Transporter subunit a2 transporter

ATP6V0A4 Atpase H+ transporting V0 5061 7 Channel or Transporter subunit a4 transporter

ATP6V0B Atpase H+ transporting V0 533 Channel or Transporter subunit b transporter

ATP6V0C Atpase H+ transporting V0 527 Channel or Transporter subunit c transporter

ATP6V0D1 Atpase H+ transporting V0 91 14 Channel or Transporter subunit d1 transporter

ATP6V0D2 Atpase H+ transporting V0 245972 Channel or Transporter subunit d2 transporter

ATP6V0E1 Atpase H+ transporting V0 8992 Channel or Transporter subunit e1 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

ATP6V0E2 Atpase H+ transporting VO 155066 Channel or Transporter subunit e2 transporter

ATP6V1 A Atpase H+ transporting V1 523 Channel or Transporter subunit A transporter

ATP6V1 B1 Atpase H+ transporting V1 525 Channel or Transporter subunit B1 transporter

ATP6V1 B2 Atpase H+ transporting V1 526 Channel or Transporter subunit B2 transporter

ATP6V1 C1 Atpase H+ transporting V1 528 Channel or Transporter subunit C1 transporter

ATP6V1 C2 Atpase H+ transporting V1 245973 Channel or Transporter subunit C2 transporter

ATP6V1 D Atpase H+ transporting V1 51382 Channel or Transporter subunit D transporter

ATP6V1 E1 Atpase H+ transporting V1 529 Channel or Transporter subunit E1 transporter

ATP6V1 E2 Atpase H+ transporting V1 90423 Channel or Transporter subunit E2 transporter

ATP6V1 F Atpase H+ transporting V1 9296 Channel or Transporter subunit F transporter

ATP6V1 G1 Atpase H+ transporting V1 9550 Channel or Transporter subunit G1 transporter

ATP6V1 G2 Atpase H+ transporting V1 534 Channel or Transporter subunit G2 transporter

ATP6V1 G3 Atpase H+ transporting V1 127124 Channel or Transporter subunit G3 transporter

ATP6V1 H Atpase H+ transporting V1 51606 Channel or Transporter subunit H transporter

ATP7A Atpase copper transporting 538 Channel or Transporter alpha transporter

ATP7B Atpase copper transporting 540 Channel or Transporter beta transporter

ATP8A1 Atpase phospholipid 10396 Channel or Transporter transporting 8A1 transporter

ATP8A2 Atpase phospholipid 51761 Channel or Transporter transporting 8A2 transporter

ATP8B1 Atpase phospholipid 5205 Channel or Transporter transporting 8B1 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

ATP8B2 Atpase phospholipid 57198 Channel or Transporter transporting 8B2 transporter

ATP8B3 Atpase phospholipid 148229 Channel or Transporter transporting 8B3 transporter

ATP8B4 Atpase phospholipid 79895 Channel or Transporter transporting 8B4 (putative) transporter

ATP9A Atpase phospholipid 10079 Channel or Transporter transporting 9A (putative) transporter

ATP9B Atpase phospholipid 374868 Channel or Transporter transporting 9B (putative) transporter

AVP Arginine vasopressin 551 Neuropeptide Ligand

AVPR1 A Arginine vasopressin receptor 552 Neuropeptide Receptor

1 A

AVPR1 B Arginine vasopressin receptor 553 Neuropeptide Receptor

1 B

AVPR2 Arginine vasopressin receptor 554 Neuropeptide Receptor

2

BACE1 Beta-secretase 1 23621 Neurotransmitter Biosynthesis

BAG2 BCL2 associated athanogene 9532 Signaling Signaling

2

BAIAP3 BAM associated protein 3 8938 Signaling Signaling

BCHE Butyrylcholinesterase 590 Neurotransmitter Biosynthesis

BCL2 BCL2, apoptosis regulator 596 Signaling Signaling

BDKRB2 Bradykinin receptor B2 624 Neuropeptide Receptor

BDNF Brain derived neurotrophic 627 Neurotrophic Ligand

factor

BDNF-AS BDNF antisense RNA 497258 Neurotrophic Ligand

BEX1 Protein BEX1 (Brain- 55859 Neurotrophic Signaling expressed X-linked protein 1 )

BEX3 Protein BEX3 (Brain- 2701 8 Neurotrophic Signaling expressed X-linked protein 3)

BRAF B-Raf proto-oncogene, 673 Signaling Signaling serine/threonine kinase

BRSK1 BR serine/threonine kinase 1 84446 Vesicular Vesicles

BSN Bassoon presynaptic 8927 Other Miscelaneous cytomatrix protein

BTBD9 BTB domain containing 9 1 14781 Vesicular Vesicles

C1 QBP Complement C1 q binding 708 Neuropeptide Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

protein

C2CD4A C2 calcium dependent domain 145741 Other Miscelaneous containing 4A

C2CD4B C2 calcium dependent domain 388125 Other Miscelaneous containing 4B

C2CD4C C2 calcium dependent domain 126567 Other Miscelaneous containing 4C

C2CD4D C2 calcium dependent domain 1001 910 Other Miscelaneous containing 4D 40

C4orf48 Chromosome 4 open reading 401 1 15 Neuropeptide Ligand

frame 48

CACNA1 A Calcium voltage-gated 773 Channel or Channel channel subunit alphal A transporter

CACNA1 B Calcium voltage-gated 774 Channel or Channel channel subunit alphal B transporter

CACNA1 C Calcium voltage-gated 775 Channel or Channel channel subunit alphal C transporter

CACNA1 D Calcium voltage-gated 776 Channel or Channel channel subunit alphal D transporter

CACNA1 E Calcium voltage-gated 777 Channel or Channel channel subunit alphal E transporter

CACNA1 F Calcium voltage-gated 778 Channel or Channel channel subunit alphal F transporter

CACNA1 G Calcium voltage-gated 8913 Channel or Channel channel subunit alphal G transporter

CACNA1 H Calcium voltage-gated 8912 Channel or Channel channel subunit alphal H transporter

CACNA1 1 Calcium voltage-gated 891 1 Channel or Channel channel subunit alphal 1 transporter

CACNA1 S Calcium voltage-gated 779 Channel or Channel channel subunit alphal S transporter

CACNB1 Calcium voltage-gated 782 Channel or Channel channel auxiliary subunit beta transporter

1

CACNB2 Calcium voltage-gated 783 Channel or Channel channel auxiliary subunit beta transporter

2

CACNB4 Calcium voltage-gated 785 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

channel auxiliary subunit beta transporter

4

CALCA Calcitonin related polypeptide 796 Neuropeptide Ligand

alpha, CGRP

CALCB Calcitonin related polypeptide 797 Neuropeptide Ligand

beta

CALCR Calcitonin receptor 799 Neuropeptide Receptor

CALCRL Calcitonin receptor like 10203 Neuropeptide Receptor receptor

CALM1 Calmodulin 1 801 Signaling Signaling

CALM2 Calmodulin 2 805 Signaling Signaling

CALM3 Calmodulin 3 808 Signaling Signaling

CALY Calcyon neuron specific 50632 Other Miscelaneous vesicular protein

CAMK2A Calcium/calmodulin 815 Signaling Signaling dependent protein kinase II

alpha

CAMK2B Calcium/calmodulin 816 Signaling Signaling dependent protein kinase II

beta

CAMK4 Calcium/calmodulin 814 Signaling Signaling dependent protein kinase IV

CARF Calcium responsive 79800 Signaling Signaling transcription factor

CARTPT CART prepropeptide 9607 Neuropeptide Ligand

CASK Calcium/calmodulin 8573 Signaling Signaling dependent serine protein

kinase

CASR Calcium sensing receptor 846 Neuropeptide Biosynthesis

CATSPER1 Cation channel sperm 1 17144 Channel or Channel associated 1 transporter

CATSPER2 Cation channel sperm 1 171 55 Channel or Channel associated 2 transporter

CATSPER3 Cation channel sperm 347732 Channel or Channel associated 3 transporter

CATSPER4 Cation channel sperm 378807 Channel or Channel associated 4 transporter

CBLN1 Cerebellin 1 precursor 869 Other Miscelaneous Approved Approved name Entrez Gene type / Category Symbol Gene ID family

CBLN2 Cerebellin 2 precursor 147381 Other Miscelaneous

CBLN3 Cerebellin 3 precursor 643866 Other Miscelaneous

CBLN4 Cerebellin 4 precursor 140689 Other Miscelaneous

CCK Cholecystokinin 885 Neuropeptide Ligand

CCKAR Cholecystokinin A receptor 886 Neuropeptide Receptor

CCKBR Cholecystokinin B receptor 887 Neuropeptide Receptor

CCL2 C-C motif chemokine ligand 2 6347 Neuropeptide Ligand

CCR1 C-C motif chemokine receptor 1230 Other Miscelaneous

1

CD34 Hematopoietic progenitor cell 947 Neurotrophic Receptor antigen CD34 (CD antigen

CD34)

CD38 CD38 molecule 952 Signaling Signaling

CDH2 Cadherin 2 1000 Signaling Signaling

CDK5 Cyclin dependent kinase 5 1020 Signaling Signaling

CDK5R1 Cyclin dependent kinase 5 8851 Signaling Signaling regulatory subunit 1

CDKN1 A Cyclin dependent kinase 1026 Signaling Signaling inhibitor 1 A

CDNF Cerebral dopamine 441549 Neurotrophic Ligand

neurotrophic factor

CHAT Choline O-acetyltransferase 1 103 Neurotransmitter Biosynthesis

CHGA Chromogranin A 1 1 13 Neuropeptide Ligand

CHGB Chromogranin B 1 1 14 Neuropeptide Ligand

CHMP4A Charged multivesicular body 29082 Vesicular Vesicles protein 4A

CHMP4B Charged multivesicular body 128866 Vesicular Vesicles protein 4B

CHRFAM7A CHRNA7 (exons 5-10) and 89832 Neurotransmitter Receptor

FAM7A (exons A-E) fusion

CHRM1 Cholinergic receptor 1 128 Neurotransmitter Receptor muscarinic 1

CHRM2 Cholinergic receptor 1 129 Neurotransmitter Receptor muscarinic 2

CHRM3 Cholinergic receptor 1 131 Neurotransmitter Receptor muscarinic 3

CHRM4 Cholinergic receptor 1 132 Neurotransmitter Receptor muscarinic 4 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

CHRM5 Cholinergic receptor 1 133 Neurotransmitter Receptor muscarinic 5

CHRNA1 Cholinergic receptor nicotinic 1 134 Neurotransmitter Receptor alpha 1 subunit

CHRNA10 Cholinergic receptor nicotinic 57053 Neurotransmitter Receptor alpha 10 subunit

CHRNA2 Cholinergic receptor nicotinic 1 135 Neurotransmitter Receptor alpha 2 subunit

CHRNA3 Cholinergic receptor nicotinic 1 136 Neurotransmitter Receptor alpha 3 subunit

CHRNA4 Cholinergic receptor nicotinic 1 137 Neurotransmitter Receptor alpha 4 subunit

CHRNA5 Cholinergic receptor nicotinic 1 138 Neurotransmitter Receptor alpha 5 subunit

CHRNA6 Cholinergic receptor nicotinic 8973 Neurotransmitter Receptor alpha 6 subunit

CHRNA7 Cholinergic receptor nicotinic 1 139 Neurotransmitter Receptor alpha 7 subunit

CHRNA9 Cholinergic receptor nicotinic 55584 Neurotransmitter Receptor alpha 9 subunit

CHRNB1 Cholinergic receptor nicotinic 1 140 Neurotransmitter Receptor beta 1 subunit

CHRNB2 Cholinergic receptor nicotinic 1 141 Neurotransmitter Receptor beta 2 subunit

CHRNB3 Cholinergic receptor nicotinic 1 142 Neurotransmitter Receptor beta 3 subunit

CHRNB4 Cholinergic receptor nicotinic 1 143 Neurotransmitter Receptor beta 4 subunit

CHRND Cholinergic receptor nicotinic 1 144 Neurotransmitter Receptor delta subunit

CHRNE Cholinergic receptor nicotinic 1 145 Neurotransmitter Receptor epsilon subunit

CHRNG Cholinergic receptor nicotinic 1 146 Neurotransmitter Receptor gamma subunit

CLCF1 Cardiotrophin-like cytokine 23529 Neuropeptide Ligand factor 1

CLCN1 Chloride voltage-gated 1 180 Channel or Channel channel 1 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

CLCN2 Chloride voltage-gated 1 181 Channel or Channel channel 2 transporter

CLCN3 Chloride voltage-gated 1 182 Channel or Channel channel 3 transporter

CLCN4 Chloride voltage-gated 1 183 Channel or Channel channel 4 transporter

CLCN5 Chloride voltage-gated 1 184 Channel or Channel channel 5 transporter

CLCN6 Chloride voltage-gated 1 185 Channel or Channel channel 6 transporter

CLCN7 Chloride voltage-gated 1 186 Channel or Channel channel 7 transporter

CLCNKA Chloride voltage-gated 1 187 Channel or Channel channel Ka transporter

CLCNKB Chloride voltage-gated 1 188 Channel or Channel channel Kb transporter

CLIC6 Chloride intracellular channel 54102 Channel or Channel

6 transporter

CLN3 CLN3, battenin 1201 Other Miscelaneous

CNGA1 Cyclic nucleotide gated 1259 Channel or Channel channel alpha 1 transporter

CNGA2 Cyclic nucleotide gated 1260 Channel or Channel channel alpha 2 transporter

CNGA3 Cyclic nucleotide gated 1261 Channel or Channel channel alpha 3 transporter

CNGA4 Cyclic nucleotide gated 1262 Channel or Channel channel alpha 4 transporter

CNGB1 Cyclic nucleotide gated 1258 Channel or Channel channel beta 1 transporter

CNGB3 Cyclic nucleotide gated 54714 Channel or Channel channel beta 3 transporter

CNR1 Cannabinoid receptor 1 1268 Neurotransmitter Receptor

CNR2 Cannabinoid receptor 2 1269 Neurotransmitter Receptor

CNRIP1 Cannabinoid receptor 25927 Neurotransmitter Receptor interacting protein 1

CNTF Ciliary neurotrophic factor 1270 Neurotrophic Ligand

CNTFR Ciliary neurotrophic factor 1271 Neurotrophic Receptor receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

CNTNAP4 Contactin associated protein 85445 Vesicular Vesicles like 4

COMT Catechol-O-methyltransferase 1312 Neurotransmitter Biosynthesis

CORT Cortistatin 1325 Neuropeptide Ligand

CPA4 Carboxypeptidase A4 51200 Neurotransmitter Biosynthesis

CPE Carboxypeptidase E 1363 Neurotransmitter Biosynthesis

CPLX1 Complexin 1 1081 5 Vesicular Vesicles

CPLX2 Complexin 2 10814 Vesicular Vesicles

CPLX3 Complexin 3 594855 Vesicular Vesicles

CPLX4 Complexin 4 339302 Vesicular Vesicles

CRCP CGRP receptor component 27297 Neuropeptide Receptor

CREB1 Camp responsive element 1385 Signaling Signaling binding protein 1

CREM Camp responsive element 1390 Neurotransmitter Signaling modulator

CRH Corticotropin releasing 1392 Neuropeptide Ligand

hormone

CRHR1 Corticotropin releasing 1394 Neuropeptide Receptor hormone receptor 1

CRHR2 Corticotropin releasing 1395 Neuropeptide Receptor hormone receptor 2

CRLF1 Cytokine receptor like factor 1 9244 Neurotrophic Receptor

CSK C-src tyrosine kinase 1445 Signaling Signaling

CSNK1 E Casein kinase 1 epsilon 1454 Signaling Signaling

CSPG5 Chondroitin sulfate 10675 Neurotrophic Ligand

proteoglycan 5

CST3 Cystatin C 1471 Other Miscelaneous

CTAGE15 CTAGE family member 15 441294 Other Miscelaneous

CTAGE4 CTAGE family member 4 1001285 Other Miscelaneous

53

CTAGE6 CTAGE family member 6 340307 Other Miscelaneous

CTAGE8 CTAGE family member 8 1001426 Other Miscelaneous

59

CTAGE9 CTAGE family member 9 643854 Other Miscelaneous

CTBP2 C-terminal binding protein 2 1488 Signaling Signaling

CTSH Cathepsin H 1512 Neuropeptide Biosynthesis

CTSV Cathepsin V 1515 Neuropeptide Biosynthesis

CXCR4 C-X-C motif chemokine 7852 Other Miscelaneous Approved Approved name Entrez Gene type / Category Symbol Gene ID family

receptor 4

CYFIP1 Cytoplasmic FMR1 interacting 23191 Signaling Signaling protein 1

CYP19A1 Cytochrome P450 family 19 1588 Other Miscelaneous subfamily A member 1

CYSLTR1 Cysteinyl leukotriene receptor 10800 Neuropeptide Receptor

1

CYSLTR2 Cysteinyl leukotriene receptor 57105 Neuropeptide Receptor

2

DAG LA Diacylglycerol lipase alpha 747 Neurotransmitter Biosynthesis

DAG LB Diacylglycerol lipase beta 221955 Neurotransmitter Biosynthesis

DBH Dopamine beta-hydroxylase 1621 Neurotransmitter Biosynthesis

DBI Diazepam binding inhibitor, 1622 Neuropeptide Ligand

acyl-coa binding protein

DCLK1 Doublecortin like kinase 1 9201 Neurotrophic Signaling

DDC Dopa decarboxylase 1644 Neurotransmitter Biosynthesis

DDR1 Discoidin domain receptor 780 Other Miscelaneous tyrosine kinase 1

DDR2 Discoidin domain receptor 4921 Other Miscelaneous tyrosine kinase 2

DGKI Diacylglycerol kinase iota 9162 Neurotransmitter Biosynthesis

DIRC2 Disrupted in renal carcinoma 2 84925 Channel or Transporter transporter

DISC1 Disrupted in schizophrenia 1 27185 Neurotrophic Signaling

DKK1 Dickkopf WNT signaling 22943 Other Miscelaneous pathway inhibitor 1

DLGAP2 DLG associated protein 2 9228 Vesicular Vesicles

DNAJC5 Dnaj heat shock protein family 80331 Neurotrophic Signaling

(Hsp40) member C5

DNM1 Dynamin 1 1759 Vesicular Vesicles

DNM2 Dynamin 2 1785 Vesicular Vesicles

DOC2A Double C2 domain alpha 8448 Signaling Signaling

DOC2B Double C2 domain beta 8447 Signaling Signaling

DPP4 Dipeptidyl peptidase 4 1803 Neurotransmitter Biosynthesis

DPYSL2 Dihydropyrimidinase like 2 1808 Neurotrophic Signaling

DRD1 Dopamine receptor D1 1812 Neurotransmitter Receptor

DRD2 Dopamine receptor D2 1813 Neurotransmitter Receptor

DRD3 Dopamine receptor D3 1814 Neurotransmitter Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

DRD4 Dopamine receptor D4 1815 Neurotransmitter Receptor

DRD5 Dopamine receptor D5 1816 Neurotransmitter Receptor

DTNA Dystrobrevin alpha 1837 Other Miscelaneous

DTNBP1 Dystrobrevin binding protein 1 84062 Other Miscelaneous

DVL1 Dishevelled segment polarity 1855 Neurotrophic Signaling protein 1

ECEL1 Endothelin converting enzyme 9427 Neurotransmitter Biosynthesis like 1

EDN1 Endothelin 1 1906 Neuropeptide Ligand

EDN2 Endothelin 2 1907 Neuropeptide Ligand

EDN3 Endothelin 3 1908 Neuropeptide Ligand

EDNRA Endothelin receptor type A 1909 Neuropeptide Receptor

EDNRB Endothelin receptor type B 1910 Neuropeptide Receptor

EEF2 Eukaryotic translation 1938 Other Miscelaneous elongation factor 2

EEF2K Eukaryotic elongation factor 2 29904 Other Miscelaneous kinase

EFNA5 Ephrin-A5 (AL-1 ) (EPH-related 1946 Neurotrophic Ligand

receptor tyrosine kinase ligand

7) (LERK-7)

EGF Epidermal growth factor 1950 Other Miscelaneous

EGFR Epidermal growth factor 1956 Other Miscelaneous receptor

EGR3 Early growth response 3 1960 Neurotrophic Signaling

EIF4A3 Eukaryotic translation initiation 9775 Other Miscelaneous factor 4A3

EIF4EBP2 Eukaryotic translation initiation 1979 Other Miscelaneous factor 4E binding protein 2

EN1 Engrailed homeobox 1 2019 Other Miscelaneous

EN02 Enolase 2 2026 Neurotrophic Signaling

EphA1 Ephrin type-A receptor 1 2041 Neurotrophic Receptor

EphAI O Ephrin type-A receptor 10 284656 Neurotrophic Receptor

EphA2 Ephrin type-A receptor 2 1969 Neurotrophic Receptor

EphA3 Ephrin type-A receptor 3 2042 Neurotrophic Receptor

EphA4 Ephrin type-A receptor 4 2043 Neurotrophic Receptor

EphA5 Ephrin type-A receptor 5 2044 Neurotrophic Receptor

EphA6 Ephrin type-A receptor 6 285220 Neurotrophic Receptor

EphA7 Ephrin type-A receptor 7 2045 Neurotrophic Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

EphA8 Ephrin type-A receptor 8 2046 Neurotrophic Receptor

EphB1 Ephrin type-B receptor 1 2047 Neurotrophic Receptor

EphB2 Ephrin type-B receptor 2 2048 Neurotrophic Receptor

EphB3 Ephrin type-B receptor 3 2049 Neurotrophic Receptor

EphB4 Ephrin type-B receptor 4 2050 Neurotrophic Receptor

EphB6 Ephrin type-B receptor 6 2051 Neurotrophic Receptor

EPO Erythropoietin 2056 Other Miscelaneous

ERBB2 Erb-b2 receptor tyrosine 2064 Other Miscelaneous kinase 2

ERC1 ELKS/RAB6-interacting/CAST 23085 Signaling Signaling family member 1

ERC2 ELKS/RAB6-interacting/CAST 26059 Signaling Signaling family member 2

ERG ERG, ETS transcription factor 2078 Other Miscelaneous

ETBR2 Receptor for prosaposin 9283 Neurotrophic Receptor

ETV5 ETS variant 5 21 19 Other Miscelaneous

EXOC3L1 Exocyst complex component 3 283849 Other Miscelaneous like 1

F2RL1 F2R like trypsin receptor 1 2150 Other Miscelaneous

FAAH Fatty acid amide hydrolase 2166 Neurotransmitter Biosynthesis

FAP Fibroblast activation protein 2191 Neuropeptide Biosynthesis alpha

FEV FEV, ETS transcription factor 54738 Other Miscelaneous

FFAR3 Free fatty acid receptor 3 2865 Other Miscelaneous

FGF14 Fibroblast growth factor 14 2259 Other Miscelaneous

FGF2 Fibroblast growth factor 2 2247 Other Miscelaneous

FGF20 Fibroblast growth factor 20 26281 Other Miscelaneous

FKBP5 FK506 binding protein 5 2289 Other Miscelaneous

FLNA Filamin A 2316 Other Miscelaneous

FLVCR1 Feline leukemia virus 28982 Channel or Transporter subgroup C cellular receptor 1 transporter

FLVCR2 Feline leukemia virus 55640 Channel or Transporter subgroup C cellular receptor transporter

family member 2

FMR1 Fragile X mental retardation 1 2332 Other Miscelaneous

FNTA Farnesyltransferase, CAAX 2339 Neurotransmitter Signaling box, alpha

FOLH1 Folate hydrolase 1 2346 Neuropeptide Biosynthesis Approved Approved name Entrez Gene type / Category Symbol Gene ID family

FRS2 Fibroblast growth factor 1081 8 Other Miscelaneous receptor substrate 2

FRS3 Fibroblast growth factor 1081 7 Other Miscelaneous receptor substrate 3

FSHR Follicle stimulating hormone 2492 Neuropeptide Receptor receptor

FSTL4 Follistatin like 4 23105 Neurotrophic Receptor

FXYD2 FXYD domain containing ion 486 Channel or Transporter transport regulator 2 transporter

GAB1 GRB2 associated binding 2549 Signaling Signaling protein 1

GABARAP GABA type A receptor- 1 1337 Neurotransmitter Receptor associated protein

GABBR1 Gamma-aminobutyric acid 2550 Neurotransmitter Receptor type B receptor subunit 1

GABRA1 Gamma-aminobutyric acid 2554 Neurotransmitter Receptor type A receptor alphal subunit

GABRA2 Gamma-aminobutyric acid 2555 Neurotransmitter Receptor type A receptor alpha2 subunit

GAB R A3 Gamma-aminobutyric acid 2556 Neurotransmitter Receptor type A receptor alpha3 subunit

GABRA4 Gamma-aminobutyric acid 2557 Neurotransmitter Receptor type A receptor alpha4 subunit

GABRA5 Gamma-aminobutyric acid 2558 Neurotransmitter Receptor type A receptor alpha5 subunit

GABRA6 Gamma-aminobutyric acid 2559 Neurotransmitter Receptor type A receptor alpha6 subunit

GABRB1 Gamma-aminobutyric acid 2560 Neurotransmitter Receptor type A receptor betal subunit

GABRB2 Gamma-aminobutyric acid 2561 Neurotransmitter Receptor type A receptor beta2 subunit

GABRB3 Gamma-aminobutyric acid 2562 Neurotransmitter Receptor type A receptor beta3 subunit

GABRD Gamma-aminobutyric acid 2563 Neurotransmitter Receptor type A receptor delta subunit

GABRE Gamma-aminobutyric acid 2564 Neurotransmitter Receptor type A receptor epsilon

subunit Approved Approved name Entrez Gene type / Category Symbol Gene ID family

GABRG1 Gamma-aminobutyric acid 2565 Neurotransmitter Receptor type A receptor gammal

subunit

GABRG2 Gamma-aminobutyric acid 2566 Neurotransmitter Receptor type A receptor gamma2

subunit

GABRG3 Gamma-aminobutyric acid 2567 Neurotransmitter Receptor type A receptor gamma3

subunit

GABRP Gamma-aminobutyric acid 2568 Neurotransmitter Receptor type A receptor pi subunit

GABRQ Gamma-aminobutyric acid 55879 Neurotransmitter Receptor type A receptor theta subunit

GABRR1 Gamma-aminobutyric acid 2569 Neurotransmitter Receptor type A receptor rhol subunit

GABRR2 Gamma-aminobutyric acid 2570 Neurotransmitter Receptor type A receptor rho2 subunit

GABRR3 Gamma-aminobutyric acid 200959 Neurotransmitter Receptor type A receptor rho3 subunit

(gene/pseudogene)

GAD1 Glutamate decarboxylase 1 2571 Neurotransmitter Biosynthesis

GAD2 Glutamate decarboxylase 2 2572 Neurotransmitter Biosynthesis

GAL Galanin and GMAP 51083 Neuropeptide Ligand

prepropeptide

GALP Galanin like peptide 85569 Neuropeptide Ligand

GALR1 Galanin receptor 1 2587 Neuropeptide Receptor

GALR2 Galanin receptor 2 881 1 Neuropeptide Receptor

GALR3 Galanin receptor 3 8484 Neuropeptide Receptor

GAST Gastrin 2520 Neuropeptide Ligand

GCGR Glucagon receptor 2642 Other Miscelaneous

GCHFR GTP cyclohydrolase I 2644 Neurotransmitter Biosynthesis feedback regulator

GDNF Glial cell derived neurotrophic 2668 Neurotrophic Ligand

factor

GFAP Glial fibrillary acidic protein 2670 Other Miscelaneous

GFRA1 GDNF family receptor alpha 1 2674 Neurotrophic Receptor

GFRA2 GDNF family receptor alpha 2 2675 Neurotrophic Receptor

GFRA3 GDNF family receptor alpha 3 2676 Neurotrophic Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

GFRA4 GDNF family receptor alpha 4 64096 Neurotrophic Receptor

GH1 Growth hormone 1 2688 Neuropeptide Ligand

GHRH Growth hormone releasing 2691 Neuropeptide Ligand hormone

GHRHR Growth hormone releasing 2692 Neuropeptide Receptor hormone receptor

GHRL Ghrelin and obestatin 51738 Neuropeptide Ligand prepropeptide

GIP Gastric inhibitory polypeptide 2695 Neuropeptide Ligand

GJA1 Gap junction protein alpha 1 2697 Channel or Channel transporter

GJA10 Gap junction protein alpha 10 84694 Channel or Channel transporter

GJA3 Gap junction protein alpha 3 2700 Channel or Channel transporter

GJA4 Gap junction protein alpha 4 2701 Channel or Channel transporter

GJA5 Gap junction protein alpha 5 2702 Channel or Channel transporter

GJA8 Gap junction protein alpha 8 2703 Channel or Channel transporter

GJA9 Gap junction protein alpha 9 81025 Channel or Channel transporter

GJB1 Gap junction protein beta 1 2705 Channel or Channel transporter

GJB2 Gap junction protein beta 2 2706 Channel or Channel transporter

GJB3 Gap junction protein beta 3 2707 Channel or Channel transporter

GJB4 Gap junction protein beta 4 127534 Channel or Channel transporter

GJB5 Gap junction protein beta 5 2709 Channel or Channel transporter

GJB6 Gap junction protein beta 6 10804 Channel or Channel transporter

GJB7 Gap junction protein beta 7 375519 Channel or Channel transporter

GJC1 Gap junction protein gamma 1 10052 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

transporter

GJC2 Gap junction protein gamma 2 57165 Channel or Channel transporter

GJC3 Gap junction protein gamma 3 349149 Channel or Channel transporter

GJD2 Gap junction protein delta 2 57369 Channel or Channel transporter

GJD3 Gap junction protein delta 3 1251 1 1 Channel or Channel transporter

GJD4 Gap junction protein delta 4 219770 Channel or Channel transporter

GJE1 Gap junction protein epsilon 1 1001265 Channel or Channel

72 transporter

GLRA1 Glycine receptor alpha 1 2741 Neurotransmitter Receptor

GLRA2 Glycine receptor alpha 2 2742 Neurotransmitter Receptor

GLRA3 Glycine receptor alpha 3 8001 Neurotransmitter Receptor

GLRA4 Glycine receptor alpha 4 441509 Neurotransmitter Receptor

GLRB Glycine receptor beta 2743 Neurotransmitter Receptor

GLS Glutaminase 2744 Neurotransmitter Biosynthesis

GLS2 Glutaminase 2 27165 Neurotransmitter Biosynthesis

GLUL Glutamate-ammonia ligase 2752 Neurotransmitter Biosynthesis

GNA1 1 G protein subunit alpha 1 1 2767 Signaling Signaling

GNA13 G protein subunit alpha 13 10672 Signaling Signaling

GNA14 G protein subunit alpha 14 9630 Signaling Signaling

GNA15 G protein subunit alpha 15 2769 Signaling Signaling

GNAI1 G protein subunit alpha i1 2770 Signaling Signaling

GNAI2 G protein subunit alpha i2 2771 Signaling Signaling

GNAI3 G protein subunit alpha i3 2773 Signaling Signaling

GNAL G protein subunit alpha L 2774 Signaling Signaling

GNA01 G protein subunit alpha o1 2775 Signaling Signaling

GNAQ G protein subunit alpha q 2776 Signaling Signaling

GNAS GNAS complex locus 2778 Signaling Signaling

GNAZ G protein subunit alpha z 2781 Signaling Signaling

GNB1 G protein subunit beta 1 2782 Signaling Signaling

GNB2 G protein subunit beta 2 2783 Signaling Signaling

GNB3 G protein subunit beta 3 2784 Signaling Signaling

GNB4 G protein subunit beta 4 59345 Signaling Signaling

GNB5 G protein subunit beta 5 10681 Signaling Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

GNG10 G protein subunit gamma 10 2790 Signaling

GNG1 1 G protein subunit gamma 1 1 2791 Signaling

GNG12 G protein subunit gamma 12 55970 Signaling Signaling

GNG13 G protein subunit gamma 13 51764 Signaling Signaling

GNG2 G protein subunit gamma 2 54331 Signaling Signaling

GNG3 G protein subunit gamma 3 2785 Signaling Signaling

GNG4 G protein subunit gamma 4 2786 Signaling

GNG5 G protein subunit gamma 5 2787 Signaling

GNG7 G protein subunit gamma 7 2788 Signaling

GNG8 G protein subunit gamma 8 94235 Signaling Signaling

GNGT2 G protein subunit gamma 2793 Signaling

transducin 2

GNMT Glycine N-methyltransferase 27232 Neurotransmitter Biosynthesis

GNRH1 Gonadotropin releasing 2796 Neuropeptide Ligand hormone 1

GNRH2 Gonadotropin releasing 2797 Neuropeptide Ligand hormone 2

GPER1 G protein-coupled estrogen 2852 Other Receptor receptor 1

GPHN Gephyrin 10243 Neuropeptide Ligand

GPI Glucose-6-phosphate 2821 Signaling Signaling isomerase

GPR1 G protein-coupled receptor 1 2825 Other Receptor

GPR139 G protein-coupled receptor 124274 Neurotransmitter Receptor

139

GPR143 G protein-coupled receptor 4935 Neurotransmitter Receptor

143

GPR149 G protein-coupled receptor 344758 Neurotransmitter Receptor

149

GPR18 G protein-coupled receptor 18 2841 Other Receptor

GPR21 G protein-coupled receptor 21 2844 Other Receptor

GPR26 G protein-coupled receptor 26 2849 Other Receptor

GPR35 G protein-coupled receptor 35 2859 Other Receptor

GPR37 Receptor for prosaposin 2861 Neurotrophic Receptor

GPR52 G protein-coupled receptor 52 9293 Neurotransmitter Receptor

GPR55 G protein-coupled receptor 55 9290 Neurotransmitter Receptor

GPR78 G protein-coupled receptor 78 27201 Neurotransmitter Receptor

GPR83 G protein-coupled receptor 83 10888 Neurotransmitter Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

GPR84 G protein-coupled receptor 84 53831 Neurotransmitter Receptor

GPRASP1 G protein-coupled receptor 9737 Neurotransmitter Receptor associated sorting protein 1

GPRC6A G protein-coupled receptor 222545 Signaling Signaling class C group 6 member A

GPRIN1 G protein regulated inducer of 1 14787 Neurotrophic Signaling neurite outgrowth 1

GPRIN2 G protein regulated inducer of 9721 Neurotrophic Signaling neurite outgrowth 2

GPRIN3 G protein regulated inducer of 285513 Neurotrophic Signaling neurite outgrowth 3

GRB2 Growth factor receptor bound 2885 Neurotrophic Signaling protein 2

GRIA1 Glutamate ionotropic receptor 2890 Neurotransmitter Receptor

AMPA type subunit 1

GRIA2 Glutamate ionotropic receptor 2891 Neurotransmitter Receptor

AMPA type subunit 2

GRIA3 Glutamate ionotropic receptor 2892 Neurotransmitter Receptor

AMPA type subunit 3

GRIA4 Glutamate ionotropic receptor 2893 Neurotransmitter Receptor

AMPA type subunit 4

GRID1 Glutamate ionotropic receptor 2894 Neurotransmitter Receptor delta type subunit 1

GRID2 Glutamate ionotropic receptor 2895 Neurotransmitter Receptor delta type subunit 2

GRIK1 Glutamate ionotropic receptor 2897 Neurotransmitter Receptor kainate type subunit 1

GRIK2 Glutamate ionotropic receptor 2898 Neurotransmitter Receptor kainate type subunit 2

GRIK3 Glutamate ionotropic receptor 2899 Neurotransmitter Receptor kainate type subunit 3

GRIK4 Glutamate ionotropic receptor 2900 Neurotransmitter Receptor kainate type subunit 4

GRIK5 Glutamate ionotropic receptor 2901 Neurotransmitter Receptor kainate type subunit 5

GRIN1 Glutamate ionotropic receptor 2902 Neurotransmitter Receptor

NMDA type subunit 1

GRIN2A Glutamate ionotropic receptor 2903 Neurotransmitter Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

NMDA type subunit 2A

GRIN2B Glutamate ionotropic receptor 2904 Neurotransmitter Receptor

NMDA type subunit 2B

GRIN2C Glutamate ionotropic receptor 2905 Neurotransmitter Receptor

NMDA type subunit 2C

GRIN2D Glutamate ionotropic receptor 2906 Neurotransmitter Receptor

NMDA type subunit 2D

GRIN3A Glutamate ionotropic receptor 1 16443 Neurotransmitter Receptor

NMDA type subunit 3A

GRIN3B Glutamate ionotropic receptor 1 16444 Neurotransmitter Receptor

NMDA type subunit 3B

GRK2 G protein-coupled receptor 156 Neurotransmitter Receptor kinase 2

GRK3 G protein-coupled receptor 157 Neurotransmitter Receptor kinase 3

GRK4 G protein-coupled receptor 2868 Signaling Signaling kinase 4

GRK5 G protein-coupled receptor 2869 Signaling Signaling kinase 5

GRM1 Glutamate metabotropic 291 1 Neurotransmitter Receptor receptor 1

GRM2 Glutamate metabotropic 2912 Neurotransmitter Receptor receptor 2

GRM3 Glutamate metabotropic 2913 Neurotransmitter Receptor receptor 3

GRM4 Glutamate metabotropic 2914 Neurotransmitter Receptor receptor 4

GRM5 Glutamate metabotropic 2915 Neurotransmitter Receptor receptor 5

GRM6 Glutamate metabotropic 2916 Neurotransmitter Receptor receptor 6

GRM7 Glutamate metabotropic 2917 Neurotransmitter Receptor receptor 7

GRM8 Glutamate metabotropic 2918 Neurotransmitter Receptor receptor 8

GRP Gastrin releasing peptide 2922 Neuropeptide Ligand

GRPR Gastrin releasing peptide 2925 Neuropeptide Receptor receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

GSK3A Glycogen synthase kinase 3 2931 Signaling Signaling alpha

GSK3B Glycogen synthase kinase 3 2932 Signaling Signaling beta

GTF2H2 General transcription factor 2966 Other Miscelaneous

IIH subunit 2

GZF1 GDNF-inducible zinc finger 64412 Neurotrophic Signaling protein 1

HAP1 Huntingtin associated protein 9001 Other Miscelaneous

1

HCN1 Hyperpolarization activated 348980 Channel or Channel cyclic nucleotide gated transporter

potassium channel 1

HCN2 Hyperpolarization activated 610 Channel or Channel cyclic nucleotide gated transporter

potassium channel 2

HCN3 Hyperpolarization activated 57657 Channel or Channel cyclic nucleotide gated transporter

potassium channel 3

HCN4 Hyperpolarization activated 10021 Channel or Channel cyclic nucleotide gated transporter

potassium channel 4

HCRT Hypocretin neuropeptide 3060 Neuropeptide Ligand

precursor

HCRTR1 Hypocretin receptor 1 3061 Neuropeptide Receptor

HCRTR2 Hypocretin receptor 2 3062 Neuropeptide Receptor

HIP1 Huntingtin interacting protein 1 3092 Other Miscelaneous

HK2 Hexokinase 2 3099 Other Miscelaneous

HMOX1 Heme oxygenase 1 3162 Other Miscelaneous

HMOX2 Heme oxygenase 2 3163 Other Miscelaneous

HNMT Histamine N- 3176 Neurotransmitter Biosynthesis methyltransferase

HOMER1 Homer scaffolding protein 1 9456 Neurotransmitter Receptor

HRAS Hras proto-oncogene, gtpase 3265 Signaling Signaling

HRH1 Histamine receptor H1 3269 Neurotransmitter Receptor

HRH2 Histamine receptor H2 3274 Neurotransmitter Receptor

HRH3 Histamine receptor H3 1 1255 Neurotransmitter Receptor

HRH4 Histamine receptor H4 59340 Neurotransmitter Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

HSPA8 Heat shock protein family A 3312 Vesicular Vesicles

(Hsp70) member 8

HTL High L-leucine transport 3343 Channel or Transporter transporter

HTR1 A 5-hydroxytryptamine receptor 3350 Neurotransmitter Receptor

1 A

HTR1 B 5-hydroxytryptamine receptor 3351 Neurotransmitter Receptor

1 B

HTR1 D 5-hydroxytryptamine receptor 3352 Neurotransmitter Receptor

1 D

HTR1 E 5-hydroxytryptamine receptor 3354 Neurotransmitter Receptor

1 E

HTR1 F 5-hydroxytryptamine receptor 3355 Neurotransmitter Receptor

1 F

HTR2A 5-hydroxytryptamine receptor 3356 Neurotransmitter Receptor

2A

HTR2B 5-hydroxytryptamine receptor 3357 Neurotransmitter Receptor

2B

HTR2C 5-hydroxytryptamine receptor 3358 Neurotransmitter Receptor

2C

HTR3A 5-hydroxytryptamine receptor 3359 Neurotransmitter Receptor

3A

HTR3B 5-hydroxytryptamine receptor 9177 Neurotransmitter Receptor

3B

HTR3C 5-hydroxytryptamine receptor 170572 Neurotransmitter Receptor

3C

HTR3D 5-hydroxytryptamine receptor 200909 Neurotransmitter Receptor

3D

HTR3E 5-hydroxytryptamine receptor 285242 Neurotransmitter Receptor

3E

HTR4 5-hydroxytryptamine receptor 3360 Neurotransmitter Receptor

4

HTR5A 5-hydroxytryptamine receptor 3361 Neurotransmitter Receptor

5A

HTR5BP 5-hydroxytryptamine receptor 645694 Neurotransmitter Receptor

5B, pseudogene

HTR6 5-hydroxytryptamine receptor 3362 Neurotransmitter Receptor

6 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

HTR7 5-hydroxytryptamine receptor 3363 Neurotransmitter Receptor

7

HTT Huntingtin 3064 Other Miscelaneous

HVCN1 Hydrogen voltage gated 84329 Channel or Channel channel 1 transporter

IAPP Islet amyloid polypeptide 3375 Neuropeptide Ligand

ICA1 Islet cell autoantigen 1 3382 Other Miscelaneous

IFNA1 Interferon alpha 1 3439 Neurotrophic Ligand

IGF1 Insulin like growth factor 1 3479 Neurotrophic Ligand

IGF2 Insulin like growth factor 2 3481 Neurotrophic Ligand

IL1 1 RA Interleukin 1 1 receptor subunit 3590 Neurotrophic Receptor alpha

IL1 B Interleukin 1 beta 3553 Neurotrophic Ligand

IL3 Interleukin 3 3562 Neurotrophic Ligand

IL4 Interleukin 4 3565 Neurotrophic Ligand

IL6 Interleukin 6 3569 Neurotrophic Ligand

IL6R Interleukin 6 receptor 3570 Neurotrophic Receptor

IL6ST Interleukin 6 signal transducer 3572 Neurotrophic Signaling

INS Insulin 3630 Neurotrophic Ligand

ITPR1 Inositol 1 ,4,5-trisphosphate 3708 Neurotransmitter Signaling receptor type 1

ITPR2 Inositol 1 ,4,5-trisphosphate 3709 Neurotransmitter Signaling receptor type 2

ITPR3 Inositol 1 ,4,5-trisphosphate 3710 Neurotransmitter Signaling receptor type 3

KALRN Kalirin, rhogef kinase 8997 Vesicular Vesicles

KCNA1 Potassium voltage-gated 3736 Channel or Channel channel subfamily A member transporter

1

KCNA10 Potassium voltage-gated 3744 Channel or Channel channel subfamily A member transporter

10

KCNA2 Potassium voltage-gated 3737 Channel or Channel channel subfamily A member transporter

2

KCNA3 Potassium voltage-gated 3738 Channel or Channel channel subfamily A member transporter

3 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

KCNA4 Potassium voltage-gated 3739 Channel or Channel channel subfamily A member transporter

4

KCNA5 Potassium voltage-gated 3741 Channel or Channel channel subfamily A member transporter

5

KCNA6 Potassium voltage-gated 3742 Channel or Channel channel subfamily A member transporter

6

KCNA7 Potassium voltage-gated 3743 Channel or Channel channel subfamily A member transporter

7

KCNAB1 Potassium voltage-gated 7881 Channel or Channel channel subfamily A member transporter

regulatory beta subunit 1

KCNAB2 Potassium voltage-gated 8514 Channel or Channel channel subfamily A transporter

regulatory beta subunit 2

KCNB1 Potassium voltage-gated 3745 Channel or Channel channel subfamily B member transporter

1

KCNB2 Potassium voltage-gated 9312 Channel or Channel channel subfamily B member transporter

2

KCNC1 Potassium voltage-gated 3746 Channel or Channel channel subfamily C member transporter

1

KCNC2 Potassium voltage-gated 3747 Channel or Channel channel subfamily C member transporter

2

KCNC3 Potassium voltage-gated 3748 Channel or Channel channel subfamily C member transporter

3

KCNC4 Potassium voltage-gated 3749 Channel or Channel channel subfamily C member transporter

4

KCND1 Potassium voltage-gated 3750 Channel or Channel channel subfamily D member transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

1

KCND2 Potassium voltage-gated 3751 Channel or Channel channel subfamily D member transporter

2

KCND3 Potassium voltage-gated 3752 Channel or Channel channel subfamily D member transporter

3

KCNE2 Potassium voltage-gated 9992 Channel or Channel channel subfamily E transporter

regulatory subunit 2

KCNE3 Potassium voltage-gated 10008 Channel or Channel channel subfamily E transporter

regulatory subunit 3

KCNE4 Potassium voltage-gated 23704 Channel or Channel channel subfamily E transporter

regulatory subunit 4

KCNF1 Potassium voltage-gated 3754 Channel or Channel channel modifier subfamily F transporter

member 1

KCNG1 Potassium voltage-gated 3755 Channel or Channel channel modifier subfamily G transporter

member 1

KCNG2 Potassium voltage-gated 26251 Channel or Channel channel modifier subfamily G transporter

member 2

KCNG3 Potassium voltage-gated 170850 Channel or Channel channel modifier subfamily G transporter

member 3

KCNG4 Potassium voltage-gated 93107 Channel or Channel channel modifier subfamily G transporter

member 4

KCNH1 Potassium voltage-gated 3756 Channel or Channel channel subfamily H member transporter

1

KCNH2 Potassium voltage-gated 3757 Channel or Channel channel subfamily H member transporter

2

KCNH3 Potassium voltage-gated 2341 6 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

channel subfamily H member transporter

3

KCNH4 Potassium voltage-gated 2341 5 Channel or Channel channel subfamily H member transporter

4

KCNH5 Potassium voltage-gated 27133 Channel or Channel channel subfamily H member transporter

5

KCNH6 Potassium voltage-gated 81033 Channel or Channel channel subfamily H member transporter

6

KCNH7 Potassium voltage-gated 90134 Channel or Channel channel subfamily H member transporter

7

KCNH8 Potassium voltage-gated 131096 Channel or Channel channel subfamily H member transporter

8

KCNJ1 Potassium voltage-gated 3758 Channel or Channel channel subfamily J member 1 transporter

KCNJ10 Potassium voltage-gated 3766 Channel or Channel channel subfamily J member transporter

10

KCNJ1 1 Potassium voltage-gated 3767 Channel or Channel channel subfamily J member transporter

1 1

KCNJ12 Potassium voltage-gated 3768 Channel or Channel channel subfamily J member transporter

12

KCNJ13 Potassium voltage-gated 3769 Channel or Channel channel subfamily J member transporter

13

KCNJ14 Potassium voltage-gated 3770 Channel or Channel channel subfamily J member transporter

14

KCNJ15 Potassium voltage-gated 3772 Channel or Channel channel subfamily J member transporter

15

KCNJ16 Potassium voltage-gated 3773 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

channel subfamily J member transporter

16

KCNJ2 Potassium voltage-gated 3759 Channel or Channel channel subfamily J member 2 transporter

KCNJ3 Potassium voltage-gated 3760 Channel or Channel channel subfamily J member 3 transporter

KCNJ4 Potassium voltage-gated 3761 Channel or Channel channel subfamily J member 4 transporter

KCNJ5 Potassium voltage-gated 3762 Channel or Channel channel subfamily J member 5 transporter

KCNJ6 Potassium voltage-gated 3763 Channel or Channel channel subfamily J member 6 transporter

KCNJ8 Potassium voltage-gated 3764 Channel or Channel channel subfamily J member 8 transporter

KCNJ9 Potassium voltage-gated 3765 Channel or Channel channel subfamily J member 9 transporter

KCNK1 Potassium two pore domain 3775 Channel or Channel channel subfamily K member transporter

1

KCNK10 Potassium two pore domain 54207 Channel or Channel channel subfamily K member transporter

10

KCNK12 Potassium two pore domain 56660 Channel or Channel channel subfamily K member transporter

12

KCNK13 Potassium two pore domain 56659 Channel or Channel channel subfamily K member transporter

13

KCNK15 Potassium two pore domain 60598 Channel or Channel channel subfamily K member transporter

15

KCNK16 Potassium two pore domain 83795 Channel or Channel channel subfamily K member transporter

16

KCNK17 Potassium two pore domain 89822 Channel or Channel channel subfamily K member transporter

17

KCNK18 Potassium two pore domain 338567 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

channel subfamily K member transporter

18

KCNK2 Potassium two pore domain 3776 Channel or Channel channel subfamily K member transporter

2

KCNK3 Potassium two pore domain 3777 Channel or Channel channel subfamily K member transporter

3

KCNK4 Potassium two pore domain 50801 Channel or Channel channel subfamily K member transporter

4

KCNK5 Potassium two pore domain 8645 Channel or Channel channel subfamily K member transporter

5

KCNK6 Potassium two pore domain 9424 Channel or Channel channel subfamily K member transporter

6

KCNK7 Potassium two pore domain 10089 Channel or Channel channel subfamily K member transporter

7

KCNK9 Potassium two pore domain 51305 Channel or Channel channel subfamily K member transporter

9

KCNMA1 Potassium calcium-activated 3778 Channel or Channel channel subfamily M alpha 1 transporter

KCNMB4 Potassium calcium-activated 27345 Channel or Channel channel subfamily M transporter

regulatory beta subunit 4

KCNN1 Potassium calcium-activated 3780 Channel or Channel channel subfamily N member transporter

1

KCNN2 Potassium calcium-activated 3781 Channel or Channel channel subfamily N member transporter

2

KCNN3 Potassium calcium-activated 3782 Channel or Channel channel subfamily N member transporter

3

KCNN4 Potassium calcium-activated 3783 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

channel subfamily N member transporter

4

KCNQ1 Potassium voltage-gated 3784 Channel or Channel channel subfamily Q member transporter

1

KCNQ2 Potassium voltage-gated 3785 Channel or Channel channel subfamily Q member transporter

2

KCNQ3 Potassium voltage-gated 3786 Channel or Channel channel subfamily Q member transporter

3

KCNQ4 Potassium voltage-gated 9132 Channel or Channel channel subfamily Q member transporter

4

KCNQ5 Potassium voltage-gated 56479 Channel or Channel channel subfamily Q member transporter

5

KCNS1 Potassium voltage-gated 3787 Channel or Channel channel modifier subfamily S transporter

member 1

KCNS2 Potassium voltage-gated 3788 Channel or Channel channel modifier subfamily S transporter

member 2

KCNS3 Potassium voltage-gated 3790 Channel or Channel channel modifier subfamily S transporter

member 3

KCNT1 Potassium sodium-activated 57582 Channel or Channel channel subfamily T member transporter

1

KCNT2 Potassium sodium-activated 343450 Channel or Channel channel subfamily T member transporter

2

KCNU1 Potassium calcium-activated 157855 Channel or Channel channel subfamily U member transporter

1

KCNV1 Potassium voltage-gated 27012 Channel or Channel channel modifier subfamily V transporter

member 1 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

KCNV2 Potassium voltage-gated 169522 Channel or Channel channel modifier subfamily V transporter

member 2

KIF1 B Kinesin family member 1 B 23095 Vesicular Vesicles

KISS1 Kiss-1 metastasis-suppressor 3814 Neuropeptide Ligand

KISS1 R KISS1 receptor 84634 Neuropeptide Receptor

KLF1 6 Kruppel like factor 16 83855 Other Miscelaneous

KRAS KRAS proto-oncogene, gtpase 3845 Signaling Signaling

L1 CAM L1 cell adhesion molecule 3897 Neurotrophic Signaling

LAMTOR3 Late endosomal/lysosomal 8649 Signaling Signaling adaptor, MAPK and MTOR

activator 3

LEP Leptin 3952 Neuropeptide Ligand

LHCGR Luteinizing 3973 Neuropeptide Receptor hormone/choriogonadotropin

receptor

LIF Leukemia inhibitory factor 3976 Neuropeptide Ligand

LIFR Leukemia inhibitory factor 3977 Neurotrophic Receptor receptor alpha

LIN7A Lin-7 homolog A, crumbs cell 8825 Vesicular Vesicles polarity complex component

LIN7B Lin-7 homolog B, crumbs cell 64130 Vesicular Vesicles polarity complex component

LIN7C Lin-7 homolog C, crumbs cell 55327 Vesicular Vesicles polarity complex component

LPAR3 Lysophosphatidic acid 23566 Other Miscelaneous receptor 3

LRP8 LDL receptor related protein 8 7804 Other Miscelaneous

LRRK2 Leucine rich repeat kinase 2 120892 Other Miscelaneous

LTB4R Leukotriene B4 receptor 1241 Other Miscelaneous

LTB4R2 Leukotriene B4 receptor 2 56413 Other Miscelaneous

LYNX1 Ly6/neurotoxin 1 66004 Neurotransmitter Receptor

MAGED1 Melanoma-associated antigen 9500 Neurotrophic Signaling

D1

MANF Mesencephalic astrocyte 7873 Neurotrophic Ligand

derived neurotrophic factor

MAOA Monoamine oxidase A 4128 Neurotransmitter Biosynthesis

MAOB Monoamine oxidase B 4129 Neurotransmitter Biosynthesis Approved Approved name Entrez Gene type / Category Symbol Gene ID family

MAP2K1 Mitogen-activated protein 5604 Signaling Signaling kinase kinase 1

MAP2K2 Mitogen-activated protein 5605 Signaling Signaling kinase kinase 2

MAP3K1 Mitogen-activated protein 4214 Signaling Signaling kinase kinase kinase 1

MAPK1 Mitogen-activated protein 5594 Signaling Signaling kinase 1

MAPK14 Mitogen-activated protein 1432 Signaling Signaling kinase 14

MAPK3 Mitogen-activated protein 5595 Signaling Signaling kinase 3

MAPK8IP2 Mitogen-activated protein 23542 Signaling Signaling kinase 8 interacting protein 2

MC1 R Melanocortin 1 receptor 4157 Neuropeptide Receptor

MC2R Melanocortin 2 receptor 4158 Neuropeptide Receptor

MC3R Melanocortin 3 receptor 4159 Neuropeptide Receptor

MC4R Melanocortin 4 receptor 4160 Neuropeptide Receptor

MC5R Melanocortin 5 receptor 4161 Neuropeptide Receptor

MCHR1 Melanin concentrating 2847 Neuropeptide Receptor hormone receptor 1

MCHR2 Melanin concentrating 84539 Neuropeptide Receptor hormone receptor 2

MCOLN1 Mucolipin 1 57192 Channel or Channel transporter

MCOLN2 Mucolipin 2 255231 Channel or Channel transporter

MCOLN3 Mucolipin 3 55283 Channel or Channel transporter

MEF2C Myocyte enhancer factor 2C 4208 Other Miscelaneous

MFSD7 Major facilitator superfamily 84179 Channel or Transporter domain containing 7 transporter

MIR204 Microrna 204 406987 Other Miscelaneous

MLN Motilin 4295 Neuropeptide Ligand

MME Membrane 431 1 Neuropeptide Biosynthesis metalloendopeptidase

MRAP Melanocortin 2 receptor 56246 Neuropeptide Receptor accessory protein Approved Approved name Entrez Gene type / Category Symbol Gene ID family

MRAP2 Melanocortin 2 receptor 1 12609 Neuropeptide Receptor accessory protein 2

MRGPRF MAS related GPR family 1 16535 Neurotransmitter Receptor member F

MRGPRX2 MAS related GPR family 1 171 94 Neurotransmitter Receptor member X2

MT3 Metallothionein 3 4504 Other Miscelaneous

MT-ATP6 Mitochondnally encoded ATP 4508 Channel or Transporter synthase 6 transporter

MT-ATP8 Mitochondrial^ encoded ATP 4509 Channel or Transporter synthase 8 transporter

MTCH1 Mitochondrial carrier 1 23787 Channel or Transporter transporter

MTCH2 Mitochondrial carrier 2 23788 Channel or Transporter transporter

MTNR1 A Melatonin receptor 1 A 4543 Neuropeptide Receptor

MTNR1 B Melatonin receptor 1 B 4544 Neuropeptide Receptor

NAAA N-acylethanolamine acid 27163 Vesicular Vesicles amidase

NAALAD2 N-acetylated alpha-linked 10003 Neuropeptide Biosynthesis acidic dipeptidase 2

NALCN Sodium leak channel, non259232 Channel or Channel selective transporter

NAMPT Nicotinamide 10135 Neurotransmitter Biosynthesis phosphoribosyltransferase

NANOGNB NANOG neighbor homeobox 360030 Vesicular Vesicles

NDNF Neuron derived neurotrophic 79625 Neurotrophic Ligand

factor

NDP NDP, norrin cystine knot 4693 Other Miscelaneous growth factor

NENF Neudesin neurotrophic factor 29937 Neurotrophic Ligand

NENFP1 Neudesin neurotrophic factor 1064802 Neurotrophic Ligand

pseudogene 1 94

NENFP2 Neudesin neurotrophic factor 1001298 Neurotrophic Ligand

pseudogene 2 80

NENFP3 Neudesin neurotrophic factor 1064817 Neurotrophic Ligand

pseudogene 3 03

NF1 Neurofibromin 1 4763 Signaling Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

NFKB1 Nuclear factor kappa B 4790 Other Miscelaneous subunit 1

NGF Nerve growth factor 4803 Neurotrophic Ligand

NGFR Nerve growth factor receptor 4804 Neurotrophic Receptor

NIPSNAP1 Nipsnap homolog 1 (C. 8508 Vesicular Vesicles

Elegans)

NISCH Nischarin 1 1 188 Neurotransmitter Receptor

NLGN1 Neuroligin 1 22871 Synaptic Synapse

NLGN2 Neuroligin 2 57555 Synaptic Synapse

NLGN3 Neuroligin 3 54413 Synaptic Synapse

NLGN4Y Neuroligin 4, Y-linked 22829 Synaptic Synapse

NMB Neuromedin B 4828 Neuropeptide Ligand

NMS Neuromedin S 129521 Neuropeptide Ligand

NMU Neuromedin U 10874 Neuropeptide Ligand

NMUR1 Neuromedin U receptor 1 1031 6 Neuropeptide Receptor

NMUR2 Neuromedin U receptor 2 56923 Neuropeptide Receptor

NOS1 Nitric oxide synthase 1 4842 Neurotransmitter Biosynthesis

NPB Neuropeptide B 256933 Neuropeptide Ligand

NPBWR1 Neuropeptides B/W receptor 1 2831 Neuropeptide Receptor

NPBWR2 Neuropeptides B/W receptor 2 2832 Neuropeptide Receptor

NPC1 L1 NPC1 like intracellular 29881 Channel or Transporter cholesterol transporter 1 transporter

NPFF Neuropeptide FF-amide 8620 Neuropeptide Ligand

peptide precursor

NPFFR1 Neuropeptide FF receptor 1 64106 Neuropeptide Receptor

NPFFR2 Neuropeptide FF receptor 2 10886 Neuropeptide Receptor

NPPA Natriuretic peptide A 4878 Neuropeptide Ligand

NPPB Natriuretic peptide B 4879 Neuropeptide Ligand

NPPC Natriuretic peptide C 4880 Neuropeptide Ligand

NPS Neuropeptide S 594857 Neuropeptide Ligand

NPSR1 Neuropeptide S receptor 1 387129 Neuropeptide Receptor

NPTN Neuroplastin 27020 Neurotransmitter Receptor

NPVF Neuropeptide VF precursor 641 1 1 Neuropeptide Ligand

NPW Neuropeptide W 283869 Neuropeptide Ligand

NPY Neuropeptide Y 4852 Neuropeptide Ligand

NPY1 R Neuropeptide Y receptor Y1 4886 Neuropeptide Receptor

NPY2R Neuropeptide Y receptor Y2 4887 Neuropeptide Receptor

NPY4R Neuropeptide Y receptor Y4 5540 Neuropeptide Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

NPY5R Neuropeptide Y receptor Y5 4889 Neuropeptide Receptor

NPY6R Neuropeptide Y receptor Y6 4888 Neuropeptide Receptor

(pseudogene)

NQ01 NAD(P)H quinone 1728 Other Miscelaneous dehydrogenase 1

NR4A2 Nuclear receptor subfamily 4 4929 Other Miscelaneous group A member 2

NRG1 Neuregulin 1 3084 Neurotrophic Ligand

NRP1 Neuropilin 1 8829 Neurotrophic Receptor

NRTN Neurturin 4902 Neurotrophic Ligand

NRXN1 Neurexin 1 9378 Synaptic Receptor

NRXN2 Neurexin 2 9379 Synaptic Receptor

NRXN3 Neurexin 3 9369 Synaptic Receptor

NSF N-ethylmaleimide sensitive 4905 Signaling Signaling factor, vesicle fusing atpase

NTF3 Neurotrophin 3 4908 Neurotrophic Ligand

NTF4 Neurotrophin 4 4909 Neurotrophic Ligand

NTRK1 Neurotrophic receptor tyrosine 4914 Neurotrophic Receptor kinase 1

NTRK2 Neurotrophic receptor tyrosine 4915 Neurotrophic Receptor kinase 2

NTRK3 Neurotrophic receptor tyrosine 4916 Neurotrophic Receptor kinase 3

NTS Neurotensin 4922 Neuropeptide Ligand

NTSR1 Neurotensin receptor 1 4923 Neuropeptide Receptor

NTSR2 Neurotensin receptor 2 23620 Neuropeptide Receptor

NUCB2 Nucleobindin 2 4925 Other Miscelaneous

NXPH1 Neurexophilin 1 3001 0 Neuropeptide Ligand

NXPH2 Neurexophilin 2 1 1249 Neuropeptide Ligand

NXPH3 Neurexophilin 3 1 1248 Neuropeptide Ligand

NXPH4 Neurexophilin 4 1 1247 Neuropeptide Ligand

OGFR Opioid growth factor receptor 1 1054 Neuropeptide Receptor

OPHN1 Oligophrenin 1 4983 Other Miscelaneous

OPRD1 Opioid receptor delta 1 4985 Neuropeptide Receptor

OPRK1 Opioid receptor kappa 1 4986 Neuropeptide Receptor

OPRL1 Opioid related nociceptin 4987 Neuropeptide Receptor receptor 1

OPRM1 Opioid receptor mu 1 4988 Neuropeptide Receptor Approved Approved name Entrez Gene type / Category Symbol Gene ID family

OTOF Otoferlin 9381 Other Miscelaneous

OXT Oxytocin/neurophysin I 5020 Neuropeptide Ligand

prepropeptide

OXTR Oxytocin receptor 5021 Neuropeptide Receptor

P2RX1 Purinergic receptor P2X 1 5023 Neurotransmitter Receptor

P2RX2 Purinergic receptor P2X 2 22953 Neurotransmitter Receptor

P2RX3 Purinergic receptor P2X 3 5024 Neurotransmitter Receptor

P2RX4 Purinergic receptor P2X 4 5025 Neurotransmitter Receptor

P2RX5 Purinergic receptor P2X 5 5026 Neurotransmitter Receptor

P2RX6 Purinergic receptor P2X 6 9127 Neurotransmitter Receptor

P2RX7 Purinergic receptor P2X 7 5027 Neurotransmitter Receptor

P2RY1 1 Purinergic receptor P2Y1 1 5032 Neurotransmitter Receptor

PAH Phenylalanine hydroxylase 5053 Neurotransmitter Biosynthesis

PANX1 Pannexin 1 24145 Channel or Channel transporter

PANX2 Pannexin 2 56666 Channel or Channel transporter

PANX3 Pannexin 3 1 16337 Channel or Channel transporter

PARK2 Parkin RBR E3 ubiquitin 5071 Other Miscelaneous protein ligase

PARK7 Parkinsonism associated 1 131 5 Other Miscelaneous deglycase

PATE4 Prostate and testis expressed 399968 Other Miscelaneous

4

PC Pyruvate carboxylase 5091 Neurotransmitter Biosynthesis

PCLO Piccolo presynaptic cytomatrix 27445 Other Miscelaneous protein

PCSK1 Proprotein convertase 5122 Neuropeptide Biosynthesis subtilisin/kexin type 1

PCSK1 N Proprotein convertase 27344 Neuropeptide Biosynthesis subtilisin/kexin type 1 inhibitor

PDE1 B Phosphodiesterase 1 B 5153 Neurotransmitter Signaling

PDE4A Phosphodiesterase 4A 5141 Neurotransmitter Signaling

PDE4D Phosphodiesterase 4D 5144 Neurotransmitter Signaling

PDK1 Pyruvate dehydrogenase 5163 Other Miscelaneous kinase 1

PDPK1 3-phosphoinositide dependent 5170 Neurotrophic Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

protein kinase 1

PDYN Prodynorphin 5173 Other Miscelaneous

PDZD1 1 PDZ domain containing 1 1 51248 Vesicular Vesicles

PENK Proenkephalin 5179 Neuropeptide Ligand

PHOX2A Paired like homeobox 2a 401 Neurotransmitter Biosynthesis

PHOX2B Paired like homeobox 2b 8929 Neurotransmitter Biosynthesis

PIK3CA Phosphatidylinositol-4,5- 5290 Neurotransmitter Signaling bisphosphate 3-kinase

catalytic subunit alpha

PIK3CB Phosphatidylinositol-4,5- 5291 Neurotransmitter Signaling bisphosphate 3-kinase

catalytic subunit beta

PIK3CG Phosphatidylinositol-4,5- 5294 Neurotransmitter Signaling bisphosphate 3-kinase

catalytic subunit gamma

PINK1 PTEN induced putative kinase 6501 8 Other Miscelaneous

1

PITX3 Paired like homeodomain 3 5309 Other Miscelaneous

PKD2 Polycystin 2, transient 531 1 Channel or Channel receptor potential cation transporter

channel

PKD2L1 Polycystin 2 like 1 , transient 9033 Channel or Channel receptor potential cation transporter

channel

PKD2L2 Polycystin 2 like 2, transient 27039 Channel or Channel receptor potential cation transporter

channel

PLAT Plasminogen activator, tissue 5327 Other Miscelaneous type

PLCB1 Phospholipase C beta 1 23236 Neurotransmitter Signaling

PLCB2 Phospholipase C beta 2 5330 Neurotransmitter Signaling

PLCB3 Phospholipase C beta 3 5331 Neurotransmitter Signaling

PLCB4 Phospholipase C beta 4 5332 Neurotransmitter Signaling

PLCD1 Phospholipase C delta 1 5333 Neurotransmitter Signaling

PLCE1 Phospholipase C epsilon 1 51 196 Neurotransmitter Signaling

PLCG1 Phospholipase C gamma 1 5335 Neurotransmitter Signaling

PLCL1 Phospholipase C like 1 5334 Neurotransmitter Signaling

PLCL2 Phospholipase C like 2 23228 Neurotransmitter Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

PLEKHH3 Pleckstrin homology, myth4 79990 Neurotrophic Signaling and FERM domain containing

H3

PMCH Pro-melanin concentrating 5367 Neuropeptide Ligand

hormone

PNKD Paroxysmal nonkinesigenic 25953 Vesicular Vesicles dyskinesia

PNOC Prepronociceptin 5368 Neuropeptide Ligand

POMC Proopiomelanocortin 5443 Neuropeptide Ligand

PPARG Peroxisome proliferator 5468 Other Miscelaneous activated receptor gamma

PPFIA1 PTPRF interacting protein 8500 Vesicular Vesicles alpha 1

PPFIA2 PTPRF interacting protein 8499 Vesicular Vesicles alpha 2

PPFIA3 PTPRF interacting protein 8541 Vesicular Vesicles alpha 3

PPFIA4 PTPRF interacting protein 8497 Vesicular Vesicles alpha 4

PPP1 CA Protein phosphatase 1 5499 Signaling Signaling catalytic subunit alpha

PPP1 CB Protein phosphatase 1 5500 Neurotransmitter Signaling catalytic subunit beta

PPP1 CC Protein phosphatase 1 5501 Neurotransmitter Signaling catalytic subunit gamma

PPP1 R12A Protein phosphatase 1 4659 Signaling Signaling regulatory subunit 12A

PPP1 R1 B Protein phosphatase 1 84152 Signaling Signaling regulatory inhibitor subunit 1 B

PPP1 R9A Protein phosphatase 1 55607 Signaling Signaling regulatory subunit 9A

PPP2CA Protein phosphatase 2 5515 Signaling Signaling catalytic subunit alpha

PPP3CA Protein phosphatase 3 5530 Signaling Signaling catalytic subunit alpha

PPP3CB Protein phosphatase 3 5532 Signaling Signaling catalytic subunit beta

PPP3CC Protein phosphatase 3 5533 Signaling Signaling Approved Approved name Entrez Gene type / Category Symbol Gene ID family

catalytic subunit gamma

PPP3R1 Protein phosphatase 3 5534 Signaling Signaling regulatory subunit B, alpha

PPP3R2 Protein phosphatase 3 5535 Signaling Signaling regulatory subunit B, beta

PPT1 Palmitoyl-protein thioesterase 5538 Other Miscelaneous

1

PPY Pancreatic polypeptide 5539 Neuropeptide Ligand

PPY2P Pancreatic polypeptide 2, 23614 Neuropeptide Ligand

pseudogene

PRIMA1 Proline rich membrane anchor 145270 Neurotransmitter Biosynthesis

1

PRKACA Protein kinase camp-activated 5566 Signaling Signaling catalytic subunit alpha

PRKACB Protein kinase camp-activated 5567 Signaling Signaling catalytic subunit beta

PRKACG Protein kinase camp-activated 5568 Neurotransmitter Signaling catalytic subunit gamma

PRKAR1 A Protein kinase camp- 5573 Signaling Signaling dependent type I regulatory

subunit alpha

PRKAR2A Protein kinase camp- 5576 Signaling Signaling dependent type II regulatory

subunit alpha

PRKAR2B Protein kinase camp- 5577 Neurotransmitter Signaling dependent type II regulatory

subunit beta

PRKCA Protein kinase C alpha 5578 Signaling Signaling

PRKCD Protein kinase C delta 5580 Signaling Signaling

PRKCE Protein kinase C epsilon 5581 Signaling Signaling

PRKCG Protein kinase C gamma 5582 Neurotransmitter Signaling

PRKX Protein kinase, X-linked 5613 Neurotransmitter Signaling

PRL Prolactin 5617 Neuropeptide Ligand

PRLH Prolactin releasing hormone 51052 Neuropeptide Ligand

PRLHR Prolactin releasing hormone 2834 Neuropeptide Receptor receptor

PRLR Prolactin receptor 5618 Neuropeptide Receptor

PROK1 Prokineticin 1 84432 Neuropeptide Ligand Approved Approved name Entrez Gene type / Category Symbol Gene ID family

PROK2 Prokineticin 2 60675 Neuropeptide Ligand

PROKR1 Prokineticin receptor 1 10887 Neuropeptide Receptor

PROKR2 Prokineticin receptor 2 128674 Neuropeptide Receptor

PROM1 Prominin 1 8842 Other Miscelaneous

PSAP Prosaposin 5660 Neurotrophic Ligand

PSEN1 Presenilin 1 5663 Neurotrophic Signaling

PSPN Persephin 5623 Neurotrophic Ligand

PTEN Phosphatase and tensin 5728 Signaling Signaling homolog

PTGDR Prostaglandin D2 receptor 5729 Neuropeptide Receptor

PTGDR2 Prostaglandin D2 receptor 2 1 1251 Neuropeptide Receptor

PTGER1 Prostaglandin E receptor 1 5731 Neuropeptide Receptor

PTGER2 Prostaglandin E receptor 2 5732 Neuropeptide Receptor

PTGER3 Prostaglandin E receptor 3 5733 Neuropeptide Receptor

PTGER4 Prostaglandin E receptor 4 5734 Neuropeptide Receptor

PTGFR Prostaglandin F receptor 5737 Neuropeptide Receptor

PTGIR Prostaglandin I2 (prostacyclin) 5739 Neuropeptide Receptor receptor (IP)

PTGS2 Prostaglandin-endoperoxide 5743 Neuropeptide Biosynthesis synthase 2

PTH Parathyroid hormone 5741 Neuropeptide Ligand

PTH1 R Parathyroid hormone 1 5745 Neuropeptide Receptor receptor

PTH2 Parathyroid hormone 2 1 13091 Neuropeptide Ligand

PTH2R Parathyroid hormone 2 5746 Neuropeptide Receptor receptor

PTHLH Parathyroid hormone like 5744 Neuropeptide Ligand

hormone

PTK2 Protein tyrosine kinase 2 5747 Neuropeptide Signaling

PTK2B Protein tyrosine kinase 2 beta 2185 Neuropeptide Signaling

PTN Pleiotrophin 5764 Neurotrophic Ligand

PTPA Protein phosphatase 2 5524 Signaling Signaling phosphatase activator

PTPRN2 Protein tyrosine phosphatase, 5799 Other Miscelaneous receptor type N2

PXK PX domain containing 54899 Vesicular Vesicles serine/threonine kinase like

PYY Peptide YY 5697 Neuropeptide Ligand Approved Approved name Entrez Gene type / Category Symbol Gene ID family

PYY2 Peptide YY 2 (pseudogene) 2361 5 Neuropeptide Ligand

PYY3 Peptide YY 3 (pseudogene) 644059 Neuropeptide Ligand

QRFP Pyroglutamylated rfamide 347148 Neuropeptide Ligand

peptide

QRFPR Pyroglutamylated rfamide 84109 Neuropeptide Receptor peptide receptor

RAB3A RAB3A, member RAS 5864 Signaling Signaling oncogene family

RAB3GAP1 RAB3 gtpase activating 22930 Vesicular Vesicles protein catalytic subunit 1

RAF1 Raf-1 proto-oncogene, 5894 Signaling Signaling serine/threonine kinase

RAM Retinoic acid induced 1 10743 Other Miscelaneous

RAMP1 Receptor activity modifying 10267 Neuropeptide Receptor protein 1

RAMP2 Receptor activity modifying 10266 Neuropeptide Receptor protein 2

RAMP3 Receptor activity modifying 10268 Neuropeptide Receptor protein 3

RAP1 A RAP1 A, member of RAS 5906 Signaling Signaling oncogene family

RAP1 GAP RAP1 gtpase activating 5909 Other Miscelaneous protein

RAPGEF2 Rap guanine nucleotide 9693 Other Miscelaneous exchange factor 2

RAPGEF3 Rap guanine nucleotide 1041 1 Signaling Signaling exchange factor 3

RAPSN Receptor associated protein of 5913 Synaptic Receptor the synapse

RELN Reelin 5649 Neurotrophic Ligand

RET Ret proto-oncogene 5979 Neurotrophic Signaling

RETN Resistin 56729 Other Miscelaneous

RETNLB Resistin like beta 84666 Other Miscelaneous

RGN Regucalcin 9104 Signaling Signaling

RGS10 Regulator of G-protein 6001 Signaling Signaling signaling 1 0

RGS8 Regulator of G-protein 85397 Signaling Signaling signaling 8 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

RGS9 Regulator of G-protein 8787 Signaling Signaling signaling 9

RHAG Rh-associated glycoprotein 6005 Channel or Transporter transporter

RHBG Rh family B glycoprotein 57127 Channel or Transporter

(gene/pseudogene) transporter

RHCG Rh family C glycoprotein 51458 Channel or Transporter transporter

RHOA Ras homolog family member 387 Signaling Signaling

A

RIC3 RIC3 acetylcholine receptor 79608 Neurotransmitter Receptor chaperone

RIC8A RIC8 guanine nucleotide 60626 Signaling Signaling exchange factor A

RIMS1 Regulating synaptic 22999 Vesicular Vesicles membrane exocytosis 1

RIMS2 Regulating synaptic 9699 Vesicular Vesicles membrane exocytosis 2

RIMS3 Regulating synaptic 9783 Vesicular Vesicles membrane exocytosis 3

RIMS4 Regulating synaptic 140730 Vesicular Vesicles membrane exocytosis 4

RLN1 Relaxin 1 6013 Neuropeptide Ligand

RLN2 Relaxin 2 6019 Neuropeptide Ligand

RLN3 Relaxin 3 1 17579 Neuropeptide Ligand

RNF40 Ring finger protein 40 9810 Other Miscelaneous

ROR1 Receptor tyrosine kinase like 4919 Neurotrophic Receptor orphan receptor 1

ROR2 Receptor tyrosine kinase like 4920 Neurotrophic Receptor orphan receptor 2

RPH3A Rabphilin 3A 22895 Vesicular Vesicles

RPH3AL Rabphilin 3A-like (without C2 9501 Vesicular Vesicles domains)

RPS6KA3 Ribosomal protein S6 kinase 6197 Neurotrophic Signaling

A3

RPSA Ribosomal protein SA 3921 Other Miscelaneous

RXFP1 Relaxin/insulin like family 59350 Neuropeptide Receptor peptide receptor 1 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

RXFP2 Relaxin/insulin like family 122042 Neuropeptide Receptor peptide receptor 2

RXFP3 Relaxin/insulin like family 51289 Neuropeptide Receptor peptide receptor 3

RXFP4 Relaxin/insulin like family 339403 Neuropeptide Receptor peptide receptor 4

RYR1 Ryanodine receptor 1 6261 Channel or Channel transporter

RYR2 Ryanodine receptor 2 6262 Channel or Channel transporter

RYR3 Ryanodine receptor 3 6263 Channel or Channel transporter

S100B S100 calcium binding protein 6285 Signaling Signaling

B

S1 PR4 Sphingosine-1 -phosphate 8698 Neuropeptide Receptor receptor 4

SCG2 Secretogranin II 7857 Neuropeptide Vesicles

SCG3 Secretogranin III 29106 Neuropeptide Vesicles

SCG5 Secretogranin V 6447 Neuropeptide Vesicles

SCN10A Sodium voltage-gated channel 6336 Channel or Channel alpha subunit 10 transporter

SCN1 1 A Sodium voltage-gated channel 1 1280 Channel or Channel alpha subunit 1 1 transporter

SCN1 A Sodium voltage-gated channel 6323 Channel or Channel alpha subunit 1 transporter

SCN1 B Sodium voltage-gated channel 6324 Channel or Channel beta subunit 1 transporter

SCN2A Sodium voltage-gated channel 6326 Channel or Channel alpha subunit 2 transporter

SCN2B Sodium voltage-gated channel 6327 Channel or Channel beta subunit 2 transporter

SCN3A Sodium voltage-gated channel 6328 Channel or Channel alpha subunit 3 transporter

SCN3B Sodium voltage-gated channel 55800 Channel or Channel beta subunit 3 transporter

SCN4A Sodium voltage-gated channel 6329 Channel or Channel alpha subunit 4 transporter

SCN4B Sodium voltage-gated channel 6330 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

beta subunit 4 transporter

SCN5A Sodium voltage-gated channel 6331 Channel or Channel alpha subunit 5 transporter

SCN7A Sodium voltage-gated channel 6332 Channel or Channel alpha subunit 7 transporter

SCN8A Sodium voltage-gated channel 6334 Channel or Channel alpha subunit 8 transporter

SCN9A Sodium voltage-gated channel 6335 Channel or Channel alpha subunit 9 transporter

SCNN1 A Sodium channel epithelial 1 6337 Channel or Channel alpha subunit transporter

SCNN1 B Sodium channel epithelial 1 6338 Channel or Channel beta subunit transporter

SCNN1 D Sodium channel epithelial 1 6339 Channel or Channel delta subunit transporter

SCNN1 G Sodium channel epithelial 1 6340 Channel or Channel gamma subunit transporter

SCT Secretin 6343 Neuropeptide Ligand

SDC3 Syndecan 3 9672 Neurotrophic Receptor

SEC14L1 SEC14 like lipid binding 1 6397 Other Miscelaneous

SEMA3E Semaphorin 3E 9723 Neurotrophic Ligand

SERPINE2 Serpin family E member 2 5270 Neurotrophic Ligand

SERPINF1 Serpin family F member 1 5176 Neurotrophic Ligand

SHANK3 SH3 and multiple ankyrin 85358 Neurotransmitter Signaling repeat domains 3

SHC1 SHC adaptor protein 1 6464 Neurotrophic Signaling

SHROOM1 Shroom family member 1 134549 Channel or Channel transporter

SHROOM2 Shroom family member 2 357 Channel or Channel transporter

SHROOM3 Shroom family member 3 5761 9 Channel or Channel transporter

SHROOM4 Shroom family member 4 57477 Channel or Channel transporter

SLC10A1 Solute carrier family 10 6554 Channel or Transporter member 1 transporter

SLC10A2 Solute carrier family 10 6555 Channel or Transporter member 2 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC10A3 Solute carrier family 10 8273 Channel or Transporter member 3 transporter

SLC10A4 Solute carrier family 10 201780 Channel or Transporter member 4 transporter

SLC10A5 Solute carrier family 10 347051 Channel or Transporter member 5 transporter

SLC10A6 Solute carrier family 10 345274 Channel or Transporter member 6 transporter

SLC10A7 Solute carrier family 10 84068 Channel or Transporter member 7 transporter

SLC1 1 A1 Solute carrier family 1 1 6556 Channel or Transporter member 1 transporter

SLC1 1 A2 Solute carrier family 1 1 4891 Channel or Transporter member 2 transporter

SLC12A1 Solute carrier family 12 6557 Channel or Transporter member 1 transporter

SLC12A2 Solute carrier family 12 6558 Channel or Transporter member 2 transporter

SLC12A3 Solute carrier family 12 6559 Channel or Transporter member 3 transporter

SLC12A4 Solute carrier family 12 6560 Channel or Transporter member 4 transporter

SLC12A5 Solute carrier family 12 57468 Channel or Transporter member 5 transporter

SLC12A6 Solute carrier family 12 9990 Channel or Transporter member 6 transporter

SLC12A7 Solute carrier family 12 10723 Channel or Transporter member 7 transporter

SLC12A8 Solute carrier family 12 84561 Channel or Transporter member 8 transporter

SLC12A9 Solute carrier family 12 56996 Channel or Transporter member 9 transporter

SLC13A1 Solute carrier family 13 6561 Channel or Transporter member 1 transporter

SLC13A2 Solute carrier family 13 9058 Channel or Transporter member 2 transporter

SLC13A3 Solute carrier family 13 64849 Channel or Transporter member 3 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC13A4 Solute carrier family 13 26266 Channel or Transporter member 4 transporter

SLC13A5 Solute carrier family 13 2841 1 1 Channel or Transporter member 5 transporter

SLC14A1 Solute carrier family 14 6563 Channel or Transporter member 1 (Kidd blood group) transporter

SLC14A2 Solute carrier family 14 8170 Channel or Transporter member 2 transporter

SLC15A1 Solute carrier family 15 6564 Channel or Transporter member 1 transporter

SLC15A2 Solute carrier family 15 6565 Channel or Transporter member 2 transporter

SLC15A3 Solute carrier family 15 51296 Channel or Transporter member 3 transporter

SLC15A4 Solute carrier family 15 121260 Channel or Transporter member 4 transporter

SLC16A1 Solute carrier family 16 6566 Channel or Transporter member 1 transporter

SLC16A10 Solute carrier family 16 1 17247 Channel or Transporter member 10 transporter

SLC16A1 1 Solute carrier family 16 162515 Channel or Transporter member 1 1 transporter

SLC16A12 Solute carrier family 16 387700 Channel or Transporter member 12 transporter

SLC16A13 Solute carrier family 16 201232 Channel or Transporter member 13 transporter

SLC16A14 Solute carrier family 16 151473 Channel or Transporter member 14 transporter

SLC16A2 Solute carrier family 16 6567 Channel or Transporter member 2 transporter

SLC16A3 Solute carrier family 16 9123 Channel or Transporter member 3 transporter

SLC16A4 Solute carrier family 16 9122 Channel or Transporter member 4 transporter

SLC16A5 Solute carrier family 16 9121 Channel or Transporter member 5 transporter

SLC16A6 Solute carrier family 16 9120 Channel or Transporter member 6 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC16A7 Solute carrier family 16 9194 Channel or Transporter member 7 transporter

SLC16A8 Solute carrier family 16 23539 Channel or Transporter member 8 transporter

SLC16A9 Solute carrier family 16 220963 Channel or Transporter member 9 transporter

SLC17A1 Solute carrier family 17 6568 Channel or Transporter member 1 transporter

SLC17A2 Solute carrier family 17 10246 Channel or Transporter member 2 transporter

SLC17A3 Solute carrier family 17 10786 Channel or Transporter member 3 transporter

SLC17A4 Solute carrier family 17 10050 Channel or Transporter member 4 transporter

SLC17A5 Solute carrier family 17 26503 Channel or Transporter member 5 transporter

SLC17A6 Solute carrier family 17 57084 Channel or Transporter member 6 transporter

SLC17A7 Solute carrier family 17 57030 Channel or Transporter member 7 transporter

SLC17A8 Solute carrier family 17 246213 Channel or Transporter member 8 transporter

SLC17A9 Solute carrier family 17 6391 0 Channel or Transporter member 9 transporter

SLC18A1 Solute carrier family 18 6570 Channel or Transporter member A1 transporter

SLC18A2 Solute carrier family 18 6571 Channel or Transporter member A2 transporter

SLC18A3 Solute carrier family 18 6572 Channel or Transporter member A3 transporter

SLC18B1 Solute carrier family 18 1 16843 Channel or Transporter member B1 transporter

SLC19A1 Solute carrier family 19 6573 Channel or Transporter member 1 transporter

SLC19A2 Solute carrier family 19 10560 Channel or Transporter member 2 transporter

SLC19A3 Solute carrier family 19 80704 Channel or Transporter member 3 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC1 A1 Solute carrier family 1 6505 Channel or Transporter member 1 transporter

SLC1 A2 Solute carrier family 1 6506 Channel or Transporter member 2 transporter

SLC1 A3 Solute carrier family 1 6507 Channel or Transporter member 3 transporter

SLC1 A6 Solute carrier family 1 651 1 Channel or Transporter member 6 transporter

SLC1 A7 Solute carrier family 1 6512 Channel or Transporter member 7 transporter

SLC20A1 Solute carrier family 20 6574 Channel or Transporter member 1 transporter

SLC20A2 Solute carrier family 20 6575 Channel or Transporter member 2 transporter

SLC22A1 Solute carrier family 22 6580 Channel or Transporter member 1 transporter

SLC22A10 Solute carrier family 22 387775 Channel or Transporter member 10 transporter

SLC22A1 1 Solute carrier family 22 55867 Channel or Transporter member 1 1 transporter

SLC22A12 Solute carrier family 22 1 16085 Channel or Transporter member 12 transporter

SLC22A13 Solute carrier family 22 9390 Channel or Transporter member 13 transporter

SLC22A14 Solute carrier family 22 9389 Channel or Transporter member 14 transporter

SLC22A15 Solute carrier family 22 55356 Channel or Transporter member 15 transporter

SLC22A16 Solute carrier family 22 85413 Channel or Transporter member 16 transporter

SLC22A17 Solute carrier family 22 5131 0 Channel or Transporter member 17 transporter

SLC22A18 Solute carrier family 22 5002 Channel or Transporter member 18 transporter

SLC22A2 Solute carrier family 22 6582 Channel or Transporter member 2 transporter

SLC22A20 Solute carrier family 22 440044 Channel or Transporter member 20 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC22A23 Solute carrier family 22 63027 Channel or Transporter member 23 transporter

SLC22A24 Solute carrier family 22 283238 Channel or Transporter member 24 transporter

SLC22A25 Solute carrier family 22 387601 Channel or Transporter member 25 transporter

SLC22A3 Solute carrier family 22 6581 Channel or Transporter member 3 transporter

SLC22A31 Solute carrier family 22 146429 Channel or Transporter member 31 transporter

SLC22A4 Solute carrier family 22 6583 Channel or Transporter member 4 transporter

SLC22A5 Solute carrier family 22 6584 Channel or Transporter member 5 transporter

SLC22A6 Solute carrier family 22 9356 Channel or Transporter member 6 transporter

SLC22A7 Solute carrier family 22 10864 Channel or Transporter member 7 transporter

SLC22A8 Solute carrier family 22 9376 Channel or Transporter member 8 transporter

SLC22A9 Solute carrier family 22 1 14571 Channel or Transporter member 9 transporter

SLC23A1 Solute carrier family 23 9963 Channel or Transporter member 1 transporter

SLC23A2 Solute carrier family 23 9962 Channel or Transporter member 2 transporter

SLC23A3 Solute carrier family 23 151295 Channel or Transporter member 3 transporter

SLC23A4P Solute carrier family 23 641842 Channel or Transporter member 4, pseudogene transporter

SLC24A1 Solute carrier family 24 9187 Channel or Transporter member 1 transporter

SLC24A2 Solute carrier family 24 25769 Channel or Transporter member 2 transporter

SLC24A3 Solute carrier family 24 5741 9 Channel or Transporter member 3 transporter

SLC24A4 Solute carrier family 24 123041 Channel or Transporter member 4 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC24A5 Solute carrier family 24 283652 Channel or Transporter member 5 transporter

SLC25A1 Solute carrier family 25 6576 Channel or Transporter member 1 transporter

SLC25A10 Solute carrier family 25 1468 Channel or Transporter member 10 transporter

SLC25A1 1 Solute carrier family 25 8402 Channel or Transporter member 1 1 transporter

SLC25A12 Solute carrier family 25 8604 Channel or Transporter member 12 transporter

SLC25A13 Solute carrier family 25 10165 Channel or Transporter member 13 transporter

SLC25A14 Solute carrier family 25 9016 Channel or Transporter member 14 transporter

SLC25A15 Solute carrier family 25 10166 Channel or Transporter member 15 transporter

SLC25A16 Solute carrier family 25 8034 Channel or Transporter member 16 transporter

SLC25A17 Solute carrier family 25 10478 Channel or Transporter member 17 transporter

SLC25A18 Solute carrier family 25 83733 Channel or Transporter member 18 transporter

SLC25A19 Solute carrier family 25 60386 Channel or Transporter member 19 transporter

SLC25A2 Solute carrier family 25 83884 Channel or Transporter member 2 transporter

SLC25A20 Solute carrier family 25 788 Channel or Transporter member 20 transporter

SLC25A21 Solute carrier family 25 89874 Channel or Transporter member 21 transporter

SLC25A22 Solute carrier family 25 79751 Channel or Transporter member 22 transporter

SLC25A23 Solute carrier family 25 79085 Channel or Transporter member 23 transporter

SLC25A24 Solute carrier family 25 29957 Channel or Transporter member 24 transporter

SLC25A25 Solute carrier family 25 1 14789 Channel or Transporter member 25 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC25A26 Solute carrier family 25 1 15286 Channel or Transporter member 26 transporter

SLC25A27 Solute carrier family 25 9481 Channel or Transporter member 27 transporter

SLC25A28 Solute carrier family 25 81894 Channel or Transporter member 28 transporter

SLC25A29 Solute carrier family 25 123096 Channel or Transporter member 29 transporter

SLC25A3 Solute carrier family 25 5250 Channel or Transporter member 3 transporter

SLC25A30 Solute carrier family 25 253512 Channel or Transporter member 30 transporter

SLC25A31 Solute carrier family 25 83447 Channel or Transporter member 31 transporter

SLC25A32 Solute carrier family 25 81034 Channel or Transporter member 32 transporter

SLC25A33 Solute carrier family 25 84275 Channel or Transporter member 33 transporter

SLC25A34 Solute carrier family 25 284723 Channel or Transporter member 34 transporter

SLC25A35 Solute carrier family 25 399512 Channel or Transporter member 35 transporter

SLC25A36 Solute carrier family 25 55186 Channel or Transporter member 36 transporter

SLC25A37 Solute carrier family 25 51312 Channel or Transporter member 37 transporter

SLC25A38 Solute carrier family 25 54977 Channel or Transporter member 38 transporter

SLC25A39 Solute carrier family 25 51629 Channel or Transporter member 39 transporter

SLC25A4 Solute carrier family 25 291 Channel or Transporter member 4 transporter

SLC25A40 Solute carrier family 25 55972 Channel or Transporter member 40 transporter

SLC25A41 Solute carrier family 25 284427 Channel or Transporter member 41 transporter

SLC25A42 Solute carrier family 25 284439 Channel or Transporter member 42 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC25A43 Solute carrier family 25 203427 Channel or Transporter member 43 transporter

SLC25A44 Solute carrier family 25 9673 Channel or Transporter member 44 transporter

SLC25A45 Solute carrier family 25 283130 Channel or Transporter member 45 transporter

SLC25A46 Solute carrier family 25 91 137 Channel or Transporter member 46 transporter

SLC25A47 Solute carrier family 25 283600 Channel or Transporter member 47 transporter

SLC25A48 Solute carrier family 25 153328 Channel or Transporter member 48 transporter

SLC25A5 Solute carrier family 25 292 Channel or Transporter member 5 transporter

SLC25A51 Solute carrier family 25 92014 Channel or Transporter member 51 transporter

SLC25A52 Solute carrier family 25 147407 Channel or Transporter member 52 transporter

SLC25A53 Solute carrier family 25 401612 Channel or Transporter member 53 transporter

SLC25A6 Solute carrier family 25 293 Channel or Transporter member 6 transporter

SLC26A1 Solute carrier family 26 10861 Channel or Transporter member 1 transporter

SLC26A10 Solute carrier family 26 65012 Channel or Transporter member 10 transporter

SLC26A1 1 Solute carrier family 26 284129 Channel or Transporter member 1 1 transporter

SLC26A2 Solute carrier family 26 1836 Channel or Transporter member 2 transporter

SLC26A3 Solute carrier family 26 181 1 Channel or Transporter member 3 transporter

SLC26A4 Solute carrier family 26 5172 Channel or Transporter member 4 transporter

SLC26A5 Solute carrier family 26 37561 1 Channel or Transporter member 5 transporter

SLC26A6 Solute carrier family 26 6501 0 Channel or Transporter member 6 transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SLC26A7 Solute carrier family 26 1 151 1 1 Channel or Transporter member 7 transporter

SLC26A8 Solute carrier family 26 1 16369 Channel or Transporter member 8 transporter

SLC26A9 Solute carrier family 26 1 15019 Channel or Transporter member 9 transporter

SLC27A1 Solute carrier family 27 376497 Channel or Transporter member 1 transporter

SLC27A2 Solute carrier family 27 1 1001 Channel or Transporter member 2 transporter

SLC27A3 Solute carrier family 27 1 1000 Channel or Transporter member 3 transporter

SLC27A4 Solute carrier family 27 10999 Channel or Transporter member 4 transporter

SLC27A5 Solute carrier family 27 10998 Channel or Transporter member 5 transporter

SLC27A6 Solute carrier family 27 28965 Channel or Transporter member 6 transporter

SLC28A1 Solute carrier family 28 9154 Channel or Transporter member 1 transporter

SLC28A2 Solute carrier family 28 9153 Channel or Transporter member 2 transporter

SLC28A3 Solute carrier family 28 64078 Channel or Transporter member 3 transporter

SLC29A1 Solute carrier family 29 2030 Channel or Transporter member 1 (Augustine blood transporter

group)

SLC29A2 Solute carrier family 29 3177 Channel or Transporter member 2 transporter

SLC29A3 Solute carrier family 29 5531 5 Channel or Transporter member 3 transporter

SLC29A4 Solute carrier family 29 222962 Channel or Transporter member 4 transporter

SLC2A1 Solute carrier family 2 6513 Channel or Transporter member 1 transporter

SLC2A10 Solute carrier family 2 81031 Channel or Transporter member 10 transporter

SLC2A1 1 Solute carrier family 2 66035 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 1 1 transporter

SLC2A12 Solute carrier family 2 154091 Channel or Transporter member 12 transporter

SLC2A13 Solute carrier family 2 1 14134 Channel or Transporter member 13 transporter

SLC2A14 Solute carrier family 2 1441 95 Channel or Transporter member 14 transporter

SLC2A2 Solute carrier family 2 6514 Channel or Transporter member 2 transporter

SLC2A3 Solute carrier family 2 6515 Channel or Transporter member 3 transporter

SLC2A4 Solute carrier family 2 6517 Channel or Transporter member 4 transporter

SLC2A5 Solute carrier family 2 6518 Channel or Transporter member 5 transporter

SLC2A6 Solute carrier family 2 1 1 182 Channel or Transporter member 6 transporter

SLC2A7 Solute carrier family 2 1551 84 Channel or Transporter member 7 transporter

SLC2A8 Solute carrier family 2 29988 Channel or Transporter member 8 transporter

SLC2A9 Solute carrier family 2 56606 Channel or Transporter member 9 transporter

SLC30A1 Solute carrier family 30 7779 Channel or Transporter member 1 transporter

SLC30A10 Solute carrier family 30 55532 Channel or Transporter member 10 transporter

SLC30A2 Solute carrier family 30 7780 Channel or Transporter member 2 transporter

SLC30A3 Solute carrier family 30 7781 Channel or Transporter member 3 transporter

SLC30A4 Solute carrier family 30 7782 Channel or Transporter member 4 transporter

SLC30A5 Solute carrier family 30 64924 Channel or Transporter member 5 transporter

SLC30A6 Solute carrier family 30 55676 Channel or Transporter member 6 transporter

SLC30A7 Solute carrier family 30 148867 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 7 transporter

SLC30A8 Solute carrier family 30 169026 Channel or Transporter member 8 transporter

SLC30A9 Solute carrier family 30 10463 Channel or Transporter member 9 transporter

SLC31 A1 Solute carrier family 31 1317 Channel or Transporter member 1 transporter

SLC31 A2 Solute carrier family 31 1318 Channel or Transporter member 2 transporter

SLC32A1 Solute carrier family 32 140679 Channel or Transporter member 1 transporter

SLC33A1 Solute carrier family 33 9197 Channel or Transporter member 1 transporter

SLC34A1 Solute carrier family 34 6569 Channel or Transporter member 1 transporter

SLC34A2 Solute carrier family 34 10568 Channel or Transporter member 2 transporter

SLC34A3 Solute carrier family 34 142680 Channel or Transporter member 3 transporter

SLC35A1 Solute carrier family 35 10559 Channel or Transporter member A1 transporter

SLC35A2 Solute carrier family 35 7355 Channel or Transporter member A2 transporter

SLC35A3 Solute carrier family 35 23443 Channel or Transporter member A3 transporter

SLC35A4 Solute carrier family 35 1 13829 Channel or Transporter member A4 transporter

SLC35A5 Solute carrier family 35 55032 Channel or Transporter member A5 transporter

SLC35B1 Solute carrier family 35 10237 Channel or Transporter member B1 transporter

SLC35B2 Solute carrier family 35 347734 Channel or Transporter member B2 transporter

SLC35B3 Solute carrier family 35 51000 Channel or Transporter member B3 transporter

SLC35B4 Solute carrier family 35 84912 Channel or Transporter member B4 transporter

SLC35C1 Solute carrier family 35 55343 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member C1 transporter

SLC35C2 Solute carrier family 35 51006 Channel or Transporter member C2 transporter

SLC35D1 Solute carrier family 35 23169 Channel or Transporter member D1 transporter

SLC35D2 Solute carrier family 35 1 1046 Channel or Transporter member D2 transporter

SLC35D3 Solute carrier family 35 340146 Channel or Transporter member D3 transporter

SLC35E1 Solute carrier family 35 79939 Channel or Transporter member E1 transporter

SLC35E2 Solute carrier family 35 9906 Channel or Transporter member E2 transporter

SLC35E2B Solute carrier family 35 728661 Channel or Transporter member E2B transporter

SLC35E3 Solute carrier family 35 55508 Channel or Transporter member E3 transporter

SLC35E4 Solute carrier family 35 339665 Channel or Transporter member E4 transporter

SLC35F1 Solute carrier family 35 222553 Channel or Transporter member F1 transporter

SLC35F2 Solute carrier family 35 54733 Channel or Transporter member F2 transporter

SLC35F3 Solute carrier family 35 148641 Channel or Transporter member F3 transporter

SLC35F4 Solute carrier family 35 341880 Channel or Transporter member F4 transporter

SLC35F5 Solute carrier family 35 80255 Channel or Transporter member F5 transporter

SLC35F6 Solute carrier family 35 54978 Channel or Transporter member F6 transporter

SLC35G1 Solute carrier family 35 159371 Channel or Transporter member G1 transporter

SLC35G2 Solute carrier family 35 80723 Channel or Transporter member G2 transporter

SLC35G3 Solute carrier family 35 146861 Channel or Transporter member G3 transporter

SLC35G4 Solute carrier family 35 646000 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member G4 transporter

SLC35G5 Solute carrier family 35 83650 Channel or Transporter member G5 transporter

SLC35G6 Solute carrier family 35 643664 Channel or Transporter member G6 transporter

SLC36A1 Solute carrier family 36 206358 Channel or Transporter member 1 transporter

SLC36A2 Solute carrier family 36 153201 Channel or Transporter member 2 transporter

SLC36A3 Solute carrier family 36 285641 Channel or Transporter member 3 transporter

SLC36A4 Solute carrier family 36 1201 03 Channel or Transporter member 4 transporter

SLC37A1 Solute carrier family 37 54020 Channel or Transporter member 1 transporter

SLC37A2 Solute carrier family 37 219855 Channel or Transporter member 2 transporter

SLC37A3 Solute carrier family 37 84255 Channel or Transporter member 3 transporter

SLC37A4 Solute carrier family 37 2542 Channel or Transporter member 4 transporter

SLC38A1 Solute carrier family 38 81539 Channel or Transporter member 1 transporter

SLC38A10 Solute carrier family 38 124565 Channel or Transporter member 10 transporter

SLC38A1 1 Solute carrier family 38 151258 Channel or Transporter member 1 1 transporter

SLC38A2 Solute carrier family 38 54407 Channel or Transporter member 2 transporter

SLC38A3 Solute carrier family 38 10991 Channel or Transporter member 3 transporter

SLC38A4 Solute carrier family 38 55089 Channel or Transporter member 4 transporter

SLC38A5 Solute carrier family 38 92745 Channel or Transporter member 5 transporter

SLC38A6 Solute carrier family 38 145389 Channel or Transporter member 6 transporter

SLC38A7 Solute carrier family 38 55238 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 7 transporter

SLC38A8 Solute carrier family 38 1461 67 Channel or Transporter member 8 transporter

SLC38A9 Solute carrier family 38 153129 Channel or Transporter member 9 transporter

SLC39A1 Solute carrier family 39 27173 Channel or Transporter member 1 transporter

SLC39A10 Solute carrier family 39 57181 Channel or Transporter member 10 transporter

SLC39A1 1 Solute carrier family 39 201266 Channel or Transporter member 1 1 transporter

SLC39A12 Solute carrier family 39 221074 Channel or Transporter member 12 transporter

SLC39A13 Solute carrier family 39 91252 Channel or Transporter member 13 transporter

SLC39A14 Solute carrier family 39 2351 6 Channel or Transporter member 14 transporter

SLC39A2 Solute carrier family 39 29986 Channel or Transporter member 2 transporter

SLC39A3 Solute carrier family 39 29985 Channel or Transporter member 3 transporter

SLC39A4 Solute carrier family 39 55630 Channel or Transporter member 4 transporter

SLC39A5 Solute carrier family 39 283375 Channel or Transporter member 5 transporter

SLC39A6 Solute carrier family 39 25800 Channel or Transporter member 6 transporter

SLC39A7 Solute carrier family 39 7922 Channel or Transporter member 7 transporter

SLC39A8 Solute carrier family 39 641 1 6 Channel or Transporter member 8 transporter

SLC39A9 Solute carrier family 39 55334 Channel or Transporter member 9 transporter

SLC3A1 Solute carrier family 3 6519 Channel or Transporter member 1 transporter

SLC3A2 Solute carrier family 3 6520 Channel or Transporter member 2 transporter

SLC40A1 Solute carrier family 40 30061 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 1 transporter

SLC41 A1 Solute carrier family 41 254428 Channel or Transporter member 1 transporter

SLC41 A2 Solute carrier family 41 84102 Channel or Transporter member 2 transporter

SLC41 A3 Solute carrier family 41 54946 Channel or Transporter member 3 transporter

SLC43A1 Solute carrier family 43 8501 Channel or Transporter member 1 transporter

SLC43A2 Solute carrier family 43 124935 Channel or Transporter member 2 transporter

SLC43A3 Solute carrier family 43 2901 5 Channel or Transporter member 3 transporter

SLC44A1 Solute carrier family 44 23446 Channel or Transporter member 1 transporter

SLC44A2 Solute carrier family 44 57153 Channel or Transporter member 2 transporter

SLC44A3 Solute carrier family 44 126969 Channel or Transporter member 3 transporter

SLC44A4 Solute carrier family 44 80736 Channel or Transporter member 4 transporter

SLC44A5 Solute carrier family 44 204962 Channel or Transporter member 5 transporter

SLC45A1 Solute carrier family 45 50651 Channel or Transporter member 1 transporter

SLC45A2 Solute carrier family 45 51 151 Channel or Transporter member 2 transporter

SLC45A3 Solute carrier family 45 85414 Channel or Transporter member 3 transporter

SLC45A4 Solute carrier family 45 5721 0 Channel or Transporter member 4 transporter

SLC46A1 Solute carrier family 46 1 13235 Channel or Transporter member 1 transporter

SLC46A2 Solute carrier family 46 57864 Channel or Transporter member 2 transporter

SLC46A3 Solute carrier family 46 283537 Channel or Transporter member 3 transporter

SLC47A1 Solute carrier family 47 55244 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 1 transporter

SLC47A2 Solute carrier family 47 146802 Channel or Transporter member 2 transporter

SLC48A1 Solute carrier family 48 55652 Channel or Transporter member 1 transporter

SLC4A1 Solute carrier family 4 6521 Channel or Transporter member 1 transporter

SLC4A10 Solute carrier family 4 57282 Channel or Transporter member 10 transporter

SLC4A1 1 Solute carrier family 4 83959 Channel or Transporter member 1 1 transporter

SLC4A2 Solute carrier family 4 6522 Channel or Transporter member 2 transporter

SLC4A3 Solute carrier family 4 6508 Channel or Transporter member 3 transporter

SLC4A4 Solute carrier family 4 8671 Channel or Transporter member 4 transporter

SLC4A5 Solute carrier family 4 57835 Channel or Transporter member 5 transporter

SLC4A7 Solute carrier family 4 9497 Channel or Transporter member 7 transporter

SLC4A8 Solute carrier family 4 9498 Channel or Transporter member 8 transporter

SLC4A9 Solute carrier family 4 83697 Channel or Transporter member 9 transporter

SLC50A1 Solute carrier family 50 55974 Channel or Transporter member 1 transporter

SLC51 A Solute carrier family 51 alpha 200931 Channel or Transporter subunit transporter

SLC51 B Solute carrier family 51 beta 123264 Channel or Transporter subunit transporter

SLC52A1 Solute carrier family 52 55065 Channel or Transporter member 1 transporter

SLC52A2 Solute carrier family 52 79581 Channel or Transporter member 2 transporter

SLC52A3 Solute carrier family 52 1 13278 Channel or Transporter member 3 transporter

SLC5A1 Solute carrier family 5 6523 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 1 transporter

SLC5A10 Solute carrier family 5 125206 Channel or Transporter member 10 transporter

SLC5A1 1 Solute carrier family 5 1 15584 Channel or Transporter member 1 1 transporter

SLC5A12 Solute carrier family 5 159963 Channel or Transporter member 12 transporter

SLC5A2 Solute carrier family 5 6524 Channel or Transporter member 2 transporter

SLC5A3 Solute carrier family 5 6526 Channel or Transporter member 3 transporter

SLC5A4 Solute carrier family 5 6527 Channel or Transporter member 4 transporter

SLC5A5 Solute carrier family 5 6528 Channel or Transporter member 5 transporter

SLC5A6 Solute carrier family 5 8884 Channel or Transporter member 6 transporter

SLC5A7 Solute carrier family 5 60482 Channel or Transporter member 7 transporter

SLC5A8 Solute carrier family 5 160728 Channel or Transporter member 8 transporter

SLC5A9 Solute carrier family 5 200010 Channel or Transporter member 9 transporter

SLC6A1 Solute carrier family 6 6529 Channel or Transporter member 1 transporter

SLC6A10P Solute carrier family 6 386757 Channel or Transporter member 10, pseudogene transporter

SLC6A10PB Solute carrier family 6 653562 Channel or Transporter member 8 pseudogene transporter

SLC6A1 1 Solute carrier family 6 6538 Channel or Transporter member 1 1 transporter

SLC6A12 Solute carrier family 6 6539 Channel or Transporter member 12 transporter

SLC6A13 Solute carrier family 6 6540 Channel or Transporter member 13 transporter

SLC6A14 Solute carrier family 6 1 1254 Channel or Transporter member 14 transporter

SLC6A15 Solute carrier family 6 551 1 7 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 15 transporter

SLC6A16 Solute carrier family 6 28968 Channel or Transporter member 16 transporter

SLC6A17 Solute carrier family 6 388662 Channel or Transporter member 17 transporter

SLC6A18 Solute carrier family 6 348932 Channel or Transporter member 18 transporter

SLC6A19 Solute carrier family 6 340024 Channel or Transporter member 19 transporter

SLC6A2 Solute carrier family 6 6530 Channel or Transporter member 2 transporter

SLC6A20 Solute carrier family 6 5471 6 Channel or Transporter member 20 transporter

SLC6A21 P Solute carrier family 6 652969 Channel or Transporter member 21 , pseudogene transporter

SLC6A3 Solute carrier family 6 6531 Channel or Transporter member 3 transporter

SLC6A4 Solute carrier family 6 6532 Channel or Transporter member 4 transporter

SLC6A5 Solute carrier family 6 9152 Channel or Transporter member 5 transporter

SLC6A6 Solute carrier family 6 6533 Channel or Transporter member 6 transporter

SLC6A7 Solute carrier family 6 6534 Channel or Transporter member 7 transporter

SLC6A8 Solute carrier family 6 6535 Channel or Transporter member 8 transporter

SLC6A9 Solute carrier family 6 6536 Channel or Transporter member 9 transporter

SLC7A1 Solute carrier family 7 6541 Channel or Transporter member 1 transporter

SLC7A10 Solute carrier family 7 56301 Channel or Transporter member 10 transporter

SLC7A1 1 Solute carrier family 7 23657 Channel or Transporter member 1 1 transporter

SLC7A13 Solute carrier family 7 157724 Channel or Transporter member 13 transporter

SLC7A14 Solute carrier family 7 57709 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 14 transporter

SLC7A2 Solute carrier family 7 6542 Channel or Transporter member 2 transporter

SLC7A3 Solute carrier family 7 84889 Channel or Transporter member 3 transporter

SLC7A4 Solute carrier family 7 6545 Channel or Transporter member 4 transporter

SLC7A5 Solute carrier family 7 8140 Channel or Transporter member 5 transporter

SLC7A6 Solute carrier family 7 9057 Channel or Transporter member 6 transporter

SLC7A7 Solute carrier family 7 9056 Channel or Transporter member 7 transporter

SLC7A8 Solute carrier family 7 23428 Channel or Transporter member 8 transporter

SLC7A9 Solute carrier family 7 1 1 136 Channel or Transporter member 9 transporter

SLC8A1 Solute carrier family 8 6546 Channel or Transporter member A1 transporter

SLC8A2 Solute carrier family 8 6543 Channel or Transporter member A2 transporter

SLC8A3 Solute carrier family 8 6547 Channel or Transporter member A3 transporter

SLC8B1 Solute carrier family 8 80024 Channel or Transporter member B1 transporter

SLC9A1 Solute carrier family 9 6548 Channel or Transporter member A1 transporter

SLC9A2 Solute carrier family 9 6549 Channel or Transporter member A2 transporter

SLC9A3 Solute carrier family 9 6550 Channel or Transporter member A3 transporter

SLC9A4 Solute carrier family 9 389015 Channel or Transporter member A4 transporter

SLC9A5 Solute carrier family 9 6553 Channel or Transporter member A5 transporter

SLC9A6 Solute carrier family 9 10479 Channel or Transporter member A6 transporter

SLC9A7 Solute carrier family 9 84679 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member A7 transporter

SLC9A8 Solute carrier family 9 2331 5 Channel or Transporter member A8 transporter

SLC9A9 Solute carrier family 9 2851 95 Channel or Transporter member A9 transporter

SLC9B1 Solute carrier family 9 1501 59 Channel or Transporter member B1 transporter

SLC9B2 Solute carrier family 9 133308 Channel or Transporter member B2 transporter

SLC9C1 Solute carrier family 9 285335 Channel or Transporter member C1 transporter

SLC9C2 Solute carrier family 9 284525 Channel or Transporter member C2 (putative) transporter

SLC01 A2 Solute carrier organic anion 6579 Channel or Transporter transporter family member transporter

1 A2

SLC01 B1 Solute carrier organic anion 10599 Channel or Transporter transporter family member transporter

1 B1

SLC01 B3 Solute carrier organic anion 28234 Channel or Transporter transporter family member transporter

1 B3

SLC01 C1 Solute carrier organic anion 5391 9 Channel or Transporter transporter family member transporter

1 C1

SLC02A1 Solute carrier organic anion 6578 Channel or Transporter transporter family member transporter

2A1

SLC02B1 Solute carrier organic anion 1 1309 Channel or Transporter transporter family member transporter

2B1

SLC03A1 Solute carrier organic anion 28232 Channel or Transporter transporter family member transporter

3A1

SLC04A1 Solute carrier organic anion 28231 Channel or Transporter transporter family member transporter

4A1

SLC04C1 Solute carrier organic anion 3531 89 Channel or Transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

transporter family member transporter

4C1

SLC05A1 Solute carrier organic anion 81796 Channel or Transporter transporter family member transporter

5A1

SLC06A1 Solute carrier organic anion 133482 Channel or Transporter transporter family member transporter

6A1

SLURP1 Secreted LY6/PLAUR domain 57152 Other Miscelaneous containing 1

SMPD3 Sphingomyelin 55512 Other Miscelaneous phosphodiesterase 3

SNAP23 Synaptosome associated 8773 Vesicular Vesicles protein 23

SNAP25 Synaptosome associated 6616 Vesicular Vesicles protein 25

SNAP29 Synaptosome associated 9342 Vesicular Vesicles protein 29

SNAPIN SNAP associated protein 23557 Signaling Signaling

SNCA Synuclein alpha 6622 Vesicular Vesicles

SNCAIP Synuclein alpha interacting 9627 Vesicular Vesicles protein

SNCB Synuclein beta 6620 Vesicular Vesicles

SNCG Synuclein gamma 6623 Vesicular Vesicles

SNPH Syntaphilin 9751 Vesicular Vesicles

SNTG1 Syntrophin gamma 1 54212 Neurotrophic Biosynthesis

SNX13 Sorting nexin 13 23161 Neurotransmitter Signaling

SOD2 Superoxide dismutase 2, 6648 Other Miscelaneous mitochondrial

SORCS1 Sortilin related VPS10 domain 1 14815 Neurotrophic Receptor containing receptor 1

SORCS2 Sortilin related VPS10 domain 57537 Neurotrophic Receptor containing receptor 2

SORCS3 Sortilin related VPS10 domain 22986 Neurotrophic Receptor containing receptor 3

SORT1 Sortilin 1 6272 Neurotrophic Receptor

SOS1 SOS Ras/Rac guanine 6654 Signaling Signaling nucleotide exchange factor 1 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SPX Spexin hormone 80763 Neuropeptide Ligand

SRC SRC proto-oncogene, non6714 Signaling Signaling receptor tyrosine kinase

SST Somatostatin 6750 Neuropeptide Ligand

SSTR1 Somatostatin receptor 1 6751 Neuropeptide Receptor

SSTR2 Somatostatin receptor 2 6752 Neuropeptide Receptor

SSTR3 Somatostatin receptor 3 6753 Neuropeptide Receptor

SSTR4 Somatostatin receptor 4 6754 Neuropeptide Receptor

SSTR5 Somatostatin receptor 5 6755 Neuropeptide Receptor

STAC3 SH3 and cysteine rich domain 246329 Other Miscelaneous

3

STRN Striatin 6801 Signaling Signaling

STX10 Syntaxin 10 8677 Vesicular Vesicles

STX1 1 Syntaxin 1 1 8676 Vesicular Vesicles

STX16 Syntaxin 16 8675 Vesicular Vesicles

STX19 Syntaxin 19 4151 17 Vesicular Vesicles

STX1 A Syntaxin 1 A 6804 Vesicular Vesicles

STX1 B Syntaxin 1 B 1 12755 Vesicular Vesicles

STX2 Syntaxin 2 2054 Vesicular Vesicles

STX3 Syntaxin 3 6809 Vesicular Vesicles

STX4 Syntaxin 4 6810 Vesicular Vesicles

STX6 Syntaxin 6 10228 Vesicular Vesicles

STXBP1 Syntaxin binding protein 1 6812 Vesicular Vesicles

STXBP5 Syntaxin binding protein 5 134957 Vesicular Vesicles

SULF1 Sulfatase 1 23213 Neurotrophic Signaling

SULF2 Sulfatase 2 55959 Neurotrophic Signaling

SV2A Synaptic vesicle glycoprotein 9900 Vesicular Vesicles

2A

SV2B Synaptic vesicle glycoprotein 9899 Vesicular Vesicles

2B

SV2C Synaptic vesicle glycoprotein 22987 Vesicular Vesicles

2C

SYN1 Synapsin I 6853 Vesicular Vesicles

SYN2 Synapsin II 6854 Vesicular Vesicles

SYN3 Synapsin III 8224 Vesicular Vesicles

SYNJ1 Synaptojanin 1 8867 Vesicular Vesicles

SYT1 Synaptotagmin 1 6857 Vesicular Vesicles

SYT10 Synaptotagmin 10 341359 Vesicular Vesicles Approved Approved name Entrez Gene type / Category Symbol Gene ID family

SYT1 1 Synaptotagmin 1 1 23208 Vesicular Vesicles

SYT12 Synaptotagmin 12 91683 Vesicular Vesicles

SYT13 Synaptotagmin 13 57586 Vesicular Vesicles

SYT14 Synaptotagmin 14 255928 Vesicular Vesicles

SYT14P1 Synaptotagmin 14 401 135 Vesicular Vesicles pseudogene 1

SYT15 Synaptotagmin 15 83849 Vesicular Vesicles

SYT16 Synaptotagmin 16 83851 Vesicular Vesicles

SYT17 Synaptotagmin 17 51760 Vesicular Vesicles

SYT2 Synaptotagmin 2 127833 Vesicular Vesicles

SYT3 Synaptotagmin 3 84258 Vesicular Vesicles

SYT4 Synaptotagmin 4 6860 Vesicular Vesicles

SYT5 Synaptotagmin 5 6861 Vesicular Vesicles

SYT6 Synaptotagmin 6 148281 Vesicular Vesicles

SYT7 Synaptotagmin 7 9066 Vesicular Vesicles

SYT8 Synaptotagmin 8 9001 9 Vesicular Vesicles

SYT9 Synaptotagmin 9 143425 Vesicular Vesicles

SYTL1 Synaptotagmin like 1 84958 Vesicular Vesicles

SYTL2 Synaptotagmin like 2 54843 Vesicular Vesicles

SYTL3 Synaptotagmin like 3 94120 Vesicular Vesicles

SYTL4 Synaptotagmin like 4 94121 Vesicular Vesicles

SYTL5 Synaptotagmin like 5 94122 Vesicular Vesicles

TAAR5 Trace amine associated 9038 Neurotransmitter Receptor receptor 5

TAC1 Tachykinin precursor 1 6863 Neuropeptide Ligand

TAC3 Tachykinin 3 6866 Neuropeptide Ligand

TAC4 Tachykinin 4 (hemokinin) 255061 Neuropeptide Ligand

TACR1 Tachykinin receptor 1 6869 Neuropeptide Receptor

TACR2 Tachykinin receptor 2 6865 Neuropeptide Receptor

TACR3 Tachykinin receptor 3 6870 Neuropeptide Receptor

TBXA2R Thromboxane A2 receptor 6915 Neuropeptide Receptor

TCIRG1 T-cell immune regulator 1 , 10312 Channel or Transporter atpase H+ transporting VO transporter

subunit a3

TENM1 Teneurin transmembrane 10178 Other Miscelaneous protein 1

TGM2 Transglutaminase 2 7052 Other Miscelaneous

TH Tyrosine hydroxylase 7054 Neurotransmitter Biosynthesis Approved Approved name Entrez Gene type / Category Symbol Gene ID family

TMEM158 Transmembrane protein 158 25907 Neurotrophic Receptor

(gene/pseudogene)

TMOD2 Tropomodulin 2 29767 Vesicular Vesicles

TNF Tumor necrosis factor 7124 Neurotrophic Ligand

TNR Tenascin R 7143 Other Miscelaneous

TP73 Tumor protein p73 7161 Other Miscelaneous

TPCN1 Two pore segment channel 1 53373 Channel or Channel transporter

TPCN2 Two pore segment channel 2 219931 Channel or Channel transporter

TPH1 Tryptophan hydroxylase 1 7166 Neurotransmitter Biosynthesis

TPH2 Tryptophan hydroxylase 2 121278 Neurotransmitter Biosynthesis

TPM3 Tropomyosin 3 7170 Neurotrophic Receptor

TPR Translocated promoter region, 7175 Other Miscelaneous nuclear basket protein

TRH Thyrotropin releasing 7200 Neuropeptide Ligand

hormone

TRHDE Thyrotropin releasing 29953 Neurotransmitter Biosynthesis hormone degrading enzyme

TRHR Thyrotropin releasing 7201 Neuropeptide Receptor hormone receptor

TRPA1 Transient receptor potential 8989 Channel or Channel cation channel subfamily A transporter

member 1

TRPC1 Transient receptor potential 7220 Channel or Channel cation channel subfamily C transporter

member 1

TRPC2 Transient receptor potential 7221 Channel or Channel cation channel subfamily C transporter

member 2, pseudogene

TRPC3 Transient receptor potential 7222 Channel or Channel cation channel subfamily C transporter

member 3

TRPC4 Transient receptor potential 7223 Channel or Channel cation channel subfamily C transporter

member 4

TRPC5 Transient receptor potential 7224 Channel or Channel cation channel subfamily C transporter Approved Approved name Entrez Gene type / Category Symbol Gene ID family

member 5

TRPC6 Transient receptor potential 7225 Channel or Channel cation channel subfamily C transporter

member 6

TRPC7 Transient receptor potential 571 13 Channel or Channel cation channel subfamily C transporter

member 7

TRPM1 Transient receptor potential 4308 Channel or Channel cation channel subfamily M transporter

member 1

TRPM2 Transient receptor potential 7226 Channel or Channel cation channel subfamily M transporter

member 2

TRPM3 Transient receptor potential 80036 Channel or Channel cation channel subfamily M transporter

member 3

TRPM4 Transient receptor potential 54795 Channel or Channel cation channel subfamily M transporter

member 4

TRPM5 Transient receptor potential 29850 Channel or Channel cation channel subfamily M transporter

member 5

TRPM6 Transient receptor potential 140803 Channel or Channel cation channel subfamily M transporter

member 6

TRPM7 Transient receptor potential 54822 Channel or Channel cation channel subfamily M transporter

member 7

TRPM8 Transient receptor potential 79054 Channel or Channel cation channel subfamily M transporter

member 8

TRPV1 Transient receptor potential 7442 Channel or Channel cation channel subfamily V transporter

member 1

TRPV2 Transient receptor potential 51393 Channel or Channel cation channel subfamily V transporter

member 2

TRPV3 Transient receptor potential 162514 Channel or Channel Approved Approved name Entrez Gene type / Category Symbol Gene ID family

cation channel subfamily V transporter

member 3

TRPV4 Transient receptor potential 59341 Channel or Channel cation channel subfamily V transporter

member 4

TRPV5 Transient receptor potential 56302 Channel or Channel cation channel subfamily V transporter

member 5

TRPV6 Transient receptor potential 55503 Channel or Channel cation channel subfamily V transporter

member 6

TSHR Thyroid stimulating hormone 7253 Neuropeptide Receptor receptor

TSPOAP1 TSPO associated protein 1 9256 Vesicular Vesicles

UBL5 Ubiquitin like 5 59286 Other Miscelaneous

UCN Urocortin 7349 Neuropeptide Ligand

UCN2 Urocortin 2 90226 Neuropeptide Ligand

UCN3 Urocortin 3 1 14131 Neuropeptide Ligand

UCP1 Uncoupling protein 1 7350 Channel or Transporter transporter

UCP2 Uncoupling protein 2 7351 Channel or Transporter transporter

UCP3 Uncoupling protein 3 7352 Channel or Transporter transporter

UNC1 1 9 Unc-1 19 lipid binding 9094 Vesicular Vesicles chaperone

UNC13A Unc-13 homolog A 23025 Vesicular Vesicles

UNC13B Unc-13 homolog B 10497 Vesicular Vesicles

USP46 Ubiquitin specific peptidase 46 64854 Other Miscelaneous

UTS2 Urotensin 2 1091 1 Neuropeptide Ligand

UTS2B Urotensin 2B 257313 Neuropeptide Ligand

UTS2R Urotensin 2 receptor 2837 Neuropeptide Receptor

VAMP1 Vesicle associated membrane 6843 Vesicular Vesicles protein 1

VAMP2 Vesicle associated membrane 6844 Vesicular Vesicles protein 2

VAMP3 Vesicle associated membrane 9341 Vesicular Vesicles protein 3 Approved Approved name Entrez Gene type / Category Symbol Gene ID family

VAMP8 Vesicle associated membrane 8673 Vesicular Vesicles

protein 8

VDAC1 Voltage dependent anion 7416 Channel or Channel

channel 1 transporter

VEGFA Vascular endothelial growth 7422 Neurotrophic Ligand

factor A

VGF VGF nerve growth factor 7425 Neurotrophic Ligand

inducible

VIP Vasoactive intestinal peptide 7432 Neuropeptide Ligand

VIPR1 Vasoactive intestinal peptide 7433 Neuropeptide Receptor

receptor 1

VIPR2 Vasoactive intestinal peptide 7434 Neuropeptide Receptor

receptor 2

XCR1 X-C motif chemokine receptor 2829 Neurotrophic Receptor

1

ZACN Zinc activated ion channel 3531 74 Channel or Channel

transporter

ZN274 Neurotrophin receptor- 10782 Neurotrophic Signaling

interacting factor homolog

Table 8: ION CHANNEL AND TRANSPORTER GENES

Lgic=ligand-gated ion channel, Vgic=voltage-gated ion channel, Other_ic=other ion channel

Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

GABRA3 Gamma-aminobutyric acid 2556 Neurotransmitter Receptor Lgic

type A receptor alpha3

subunit

GABRA4 Gamma-aminobutyric acid 2557 Neurotransmitter Receptor Lgic

type A receptor alpha4

subunit

GABRA5 Gamma-aminobutyric acid 2558 Neurotransmitter Receptor Lgic

type A receptor alpha5

subunit

GABRA6 Gamma-aminobutyric acid 2559 Neurotransmitter Receptor Lgic

type A receptor alpha6

subunit

GABRB1 Gamma-aminobutyric acid 2560 Neurotransmitter Receptor Lgic

type A receptor betal

subunit

GABRB2 Gamma-aminobutyric acid 2561 Neurotransmitter Receptor Lgic

type A receptor beta2

subunit

GABRB3 Gamma-aminobutyric acid 2562 Neurotransmitter Receptor Lgic

type A receptor beta3

subunit

GABRD Gamma-aminobutyric acid 2563 Neurotransmitter Receptor Lgic

type A receptor delta

subunit

GABRE Gamma-aminobutyric acid 2564 Neurotransmitter Receptor Lgic

type A receptor epsilon

subunit

GABRG1 Gamma-aminobutyric acid 2565 Neurotransmitter Receptor Lgic

type A receptor gammal

subunit

GABRG2 Gamma-aminobutyric acid 2566 Neurotransmitter Receptor Lgic

type A receptor gamma2

subunit

GABRG3 Gamma-aminobutyric acid 2567 Neurotransmitter Receptor Lgic

type A receptor gamma3

subunit

GABRP Gamma-aminobutyric acid 2568 Neurotransmitter Receptor Lgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type type A receptor pi subunit

GABRQ Gamma-aminobutyric acid 55879 Neurotransmitter Receptor Lgic

type A receptor theta

subunit

GABRR1 Gamma-aminobutyric acid 2569 Neurotransmitter Receptor Lgic

type A receptor rhol subunit

GABRR2 Gamma-aminobutyric acid 2570 Neurotransmitter Receptor Lgic

type A receptor rho2 subunit

GABRR3 Gamma-aminobutyric acid 200959 Neurotransmitter Receptor Lgic

type A receptor rho3 subunit

(gene/pseudogene)

GLRA1 Glycine receptor alpha 1 2741 Neurotransmitter Receptor Lgic

GLRA2 Glycine receptor alpha 2 2742 Neurotransmitter Receptor Lgic

GLRA3 Glycine receptor alpha 3 8001 Neurotransmitter Receptor Lgic

GLRA4 Glycine receptor alpha 4 441509 Neurotransmitter Receptor Lgic

GLRB Glycine receptor beta 2743 Neurotransmitter Receptor Lgic

GRIA1 Glutamate ionotropic 2890 Neurotransmitter Receptor Lgic

receptor AMPA type subunit

1

GRIA2 Glutamate ionotropic 2891 Neurotransmitter Receptor Lgic

receptor AMPA type subunit

2

GRIA3 Glutamate ionotropic 2892 Neurotransmitter Receptor Lgic

receptor AMPA type subunit

3

GRIA4 Glutamate ionotropic 2893 Neurotransmitter Receptor Lgic

receptor AMPA type subunit

4

GRID1 Glutamate ionotropic 2894 Neurotransmitter Receptor Lgic

receptor delta type subunit

1

GRID2 Glutamate ionotropic 2895 Neurotransmitter Receptor Lgic

receptor delta type subunit

2

GRIK1 Glutamate ionotropic 2897 Neurotransmitter Receptor Lgic

receptor kainate type

subunit 1 Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

GRIK2 Glutamate ionotropic 2898 Neurotransmitter Receptor Lgic

receptor kainate type

subunit 2

GRIK3 Glutamate ionotropic 2899 Neurotransmitter Receptor Lgic

receptor kainate type

subunit 3

GRIK4 Glutamate ionotropic 2900 Neurotransmitter Receptor Lgic

receptor kainate type

subunit 4

GRIK5 Glutamate ionotropic 2901 Neurotransmitter Receptor Lgic

receptor kainate type

subunit 5

GRIN1 Glutamate ionotropic 2902 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

1

GRIN2A Glutamate ionotropic 2903 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

2A

GRIN2B Glutamate ionotropic 2904 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

2B

GRIN2C Glutamate ionotropic 2905 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

2C

GRIN2D Glutamate ionotropic 2906 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

2D

GRIN3A Glutamate ionotropic 1 16443 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

3A

GRIN3B Glutamate ionotropic 1 16444 Neurotransmitter Receptor Lgic

receptor NMDA type subunit

3B

HTR3A 5-hydroxytryptamine 3359 Neurotransmitter Receptor Lgic

receptor 3A

HTR3B 5-hydroxytryptamine 9177 Neurotransmitter Receptor Lgic

receptor 3B Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

HTR3C 5-hydroxytryptamine 170572 Neurotransmitter Receptor Lgic

receptor 3C

HTR3D 5-hydroxytryptamine 200909 Neurotransmitter Receptor Lgic

receptor 3D

HTR3E 5-hydroxytryptamine 285242 Neurotransmitter Receptor Lgic

receptor 3E

ITPR1 Inositol 1 ,4,5-trisphosphate 3708 Neurotransmitter Signaling Lgic

receptor type 1

ITPR2 Inositol 1 ,4,5-trisphosphate 3709 Neurotransmitter Signaling Lgic

receptor type 2

ITPR3 Inositol 1 ,4,5-trisphosphate 3710 Neurotransmitter Signaling Lgic

receptor type 3

SCNN1 A Sodium channel epithelial 1 6337 Channel or Channel Lgic

alpha subunit transporter

SCNN1 B Sodium channel epithelial 1 6338 Channel or Channel Lgic

beta subunit transporter

SCNN1 D Sodium channel epithelial 1 6339 Channel or Channel Lgic

delta subunit transporter

SCNN1 G Sodium channel epithelial 1 6340 Channel or Channel Lgic

gamma subunit transporter

ZACN Zinc activated ion channel 3531 74 Channel or Channel Lgic

transporter

CLCN1 Chloride voltage-gated 1 180 Channel or Channel Otherjc channel 1 transporter

CLCN2 Chloride voltage-gated 1 181 Channel or Channel Otherjc channel 2 transporter

CLCN3 Chloride voltage-gated 1 182 Channel or Channel Otherjc channel 3 transporter

CLCN4 Chloride voltage-gated 1 183 Channel or Channel Otherjc channel 4 transporter

CLCN5 Chloride voltage-gated 1 184 Channel or Channel Otherjc channel 5 transporter

CLCN6 Chloride voltage-gated 1 185 Channel or Channel Otherjc channel 6 transporter

CLCN7 Chloride voltage-gated 1 186 Channel or Channel Otherjc channel 7 transporter

CLCNKA Chloride voltage-gated 1 187 Channel or Channel Otherjc Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type channel Ka transporter

CLCNKB Chloride voltage-gated 1 188 Channel or Channel Otherjc channel Kb transporter

CLIC6 Chloride intracellular 54102 Channel or Channel Otherjc channel 6 transporter

GJA1 Gap junction protein alpha 1 2697 Channel or Channel Otherjc transporter

GJA10 Gap junction protein alpha 84694 Channel or Channel Otherjc

10 transporter

GJA3 Gap junction protein alpha 3 2700 Channel or Channel Otherjc transporter

GJA4 Gap junction protein alpha 4 2701 Channel or Channel Otherjc transporter

GJA5 Gap junction protein alpha 5 2702 Channel or Channel Otherjc transporter

GJA8 Gap junction protein alpha 8 2703 Channel or Channel Otherjc transporter

GJA9 Gap junction protein alpha 9 81025 Channel or Channel Otherjc transporter

GJB1 Gap junction protein beta 1 2705 Channel or Channel Otherjc transporter

GJB2 Gap junction protein beta 2 2706 Channel or Channel Otherjc transporter

GJB3 Gap junction protein beta 3 2707 Channel or Channel Otherjc transporter

GJB4 Gap junction protein beta 4 127534 Channel or Channel Otherjc transporter

GJB5 Gap junction protein beta 5 2709 Channel or Channel Otherjc transporter

GJB6 Gap junction protein beta 6 10804 Channel or Channel Otherjc transporter

GJB7 Gap junction protein beta 7 375519 Channel or Channel Otherjc transporter

GJC1 Gap junction protein gamma 10052 Channel or Channel Otherjc

1 transporter

GJC2 Gap junction protein gamma 57165 Channel or Channel Otherjc

2 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

GJC3 Gap junction protein gamma 349149 Channel or Channel Otherjc

3 transporter

GJD2 Gap junction protein delta 2 57369 Channel or Channel Otherjc transporter

GJD3 Gap junction protein delta 3 1251 1 1 Channel or Channel Otherjc transporter

GJD4 Gap junction protein delta 4 219770 Channel or Channel Otherjc transporter

GJE1 Gap junction protein epsilon 100126572 Channel or Channel Otherjc

1 transporter

KCNMB4 Potassium calcium- 27345 Channel or Channel Otherjc activated channel subfamily transporter

M regulatory beta subunit 4

NALCN Sodium leak channel, non259232 Channel or Channel Otherjc selective transporter

PANX1 Pannexin 1 24145 Channel or Channel Otherjc transporter

PANX2 Pannexin 2 56666 Channel or Channel Otherjc transporter

PANX3 Pannexin 3 1 16337 Channel or Channel Otherjc transporter

SHROOM1 Shroom family member 1 134549 Channel or Channel Otherjc transporter

SHROOM2 Shroom family member 2 357 Channel or Channel Otherjc transporter

SHROOM3 Shroom family member 3 5761 9 Channel or Channel Otherjc transporter

SHROOM4 Shroom family member 4 57477 Channel or Channel Otherjc transporter

ATP10A Atpase phospholipid 57194 Channel or Transporter Transporter transporting 10A (putative) transporter

ATP10B Atpase phospholipid 23120 Channel or Transporter Transporter transporting 10B (putative) transporter

ATP10D Atpase phospholipid 57205 Channel or Transporter Transporter transporting 10D (putative) transporter

ATP1 1 A Atpase phospholipid 23250 Channel or Transporter Transporter transporting 1 1 A transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

ATP1 1 B Atpase phospholipid 23200 Channel or Transporter Transporter transporting 1 1 B (putative) transporter

ATP1 1 C Atpase phospholipid 286410 Channel or Transporter Transporter transporting 1 1 C transporter

ATP12A Atpase H+/K+ transporting 479 Channel or Transporter Transporter non-gastric alpha2 subunit transporter

ATP1 A1 Atpase Na+/K+ transporting 476 Channel or Transporter Transporter subunit alpha 1 transporter

ATP1 A2 Atpase Na+/K+ transporting 477 Channel or Transporter Transporter subunit alpha 2 transporter

ATP 1 A3 Atpase Na+/K+ transporting 478 Channel or Transporter Transporter subunit alpha 3 transporter

ATP1 A4 Atpase Na+/K+ transporting 480 Channel or Transporter Transporter subunit alpha 4 transporter

ATP1 B1 Atpase Na+/K+ transporting 481 Channel or Transporter Transporter subunit beta 1 transporter

ATP1 B2 Atpase Na+/K+ transporting 482 Channel or Transporter Transporter subunit beta 2 transporter

ATP1 B3 Atpase Na+/K+ transporting 483 Channel or Transporter Transporter subunit beta 3 transporter

ATP2A1 Atpase 487 Channel or Transporter Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting

1

ATP2A2 Atpase 488 Channel or Transporter Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting

2

ATP2A3 Atpase 489 Channel or Transporter Transporter sarcoplasmic/endoplasmic transporter

reticulum Ca2+ transporting

3

ATP2B1 Atpase plasma membrane 490 Channel or Transporter Transporter

Ca2+ transporting 1 transporter

ATP2B2 Atpase plasma membrane 491 Channel or Transporter Transporter

Ca2+ transporting 2 transporter

ATP2B3 Atpase plasma membrane 492 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

Ca2+ transporting 3 transporter

ATP2B4 Atpase plasma membrane 493 Channel or Transporter Transporter

Ca2+ transporting 4 transporter

ATP2C1 Atpase secretory pathway 27032 Channel or Transporter Transporter

Ca2+ transporting 1 transporter

ATP2C2 Atpase secretory pathway 9914 Channel or Transporter Transporter

Ca2+ transporting 2 transporter

ATP4A Atpase H+/K+ transporting 495 Channel or Transporter Transporter alpha subunit transporter

ATP4B Atpase H+/K+ transporting 496 Channel or Transporter Transporter beta subunit transporter

ATP5A1 ATP synthase, H+ 498 Channel or Transporter Transporter transporting, mitochondrial transporter

F1 complex, alpha subunit

1 , cardiac muscle

ATP5B ATP synthase, H+ 506 Channel or Transporter Transporter transporting, mitochondrial transporter

F1 complex, beta

polypeptide

ATP5C1 ATP synthase, H+ 509 Channel or Transporter Transporter transporting, mitochondrial transporter

F1 complex, gamma

polypeptide 1

ATP5D ATP synthase, H+ 513 Channel or Transporter Transporter transporting, mitochondrial transporter

F1 complex, delta subunit

ATP5E ATP synthase, H+ 514 Channel or Transporter Transporter transporting, mitochondrial transporter

F1 complex, epsilon subunit

ATP5F1 ATP synthase, H+ 515 Channel or Transporter Transporter transporting, mitochondrial transporter

Fo complex subunit B1

ATP5H ATP synthase, H+ 10476 Channel or Transporter Transporter transporting, mitochondrial transporter

Fo complex subunit D

ATP5I ATP synthase, H+ 521 Channel or Transporter Transporter transporting, mitochondrial transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

Fo complex subunit E

ATP5J ATP synthase, H+ 522 Channel or Transporter Transporter transporting, mitochondrial transporter

Fo complex subunit F6

ATP5J2 ATP synthase, H+ 9551 Channel or Transporter Transporter transporting, mitochondrial transporter

Fo complex subunit F2

ATP5L2 ATP synthase, H+ 267020 Channel or Transporter Transporter transporting, mitochondrial transporter

Fo complex subunit G2

ATP6V0A1 Atpase H+ transporting VO 535 Channel or Transporter Transporter subunit a1 transporter

ATP6V0A2 Atpase H+ transporting VO 23545 Channel or Transporter Transporter subunit a2 transporter

ATP6V0A4 Atpase H+ transporting VO 5061 7 Channel or Transporter Transporter subunit a4 transporter

ATP6V0B Atpase H+ transporting VO 533 Channel or Transporter Transporter subunit b transporter

ATP6V0C Atpase H+ transporting VO 527 Channel or Transporter Transporter subunit c transporter

ATP6V0D1 Atpase H+ transporting VO 91 14 Channel or Transporter Transporter subunit d1 transporter

ATP6V0D2 Atpase H+ transporting VO 245972 Channel or Transporter Transporter subunit d2 transporter

ATP6V0E1 Atpase H+ transporting VO 8992 Channel or Transporter Transporter subunit e1 transporter

ATP6V0E2 Atpase H+ transporting VO 155066 Channel or Transporter Transporter subunit e2 transporter

ATP6V1 A Atpase H+ transporting V1 523 Channel or Transporter Transporter subunit A transporter

ATP6V1 B1 Atpase H+ transporting V1 525 Channel or Transporter Transporter subunit B1 transporter

ATP6V1 B2 Atpase H+ transporting V1 526 Channel or Transporter Transporter subunit B2 transporter

ATP6V1 C1 Atpase H+ transporting V1 528 Channel or Transporter Transporter subunit C1 transporter

ATP6V1 C2 Atpase H+ transporting V1 245973 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type subunit C2 transporter

ATP6V1 D Atpase H+ transporting V1 51382 Channel or Transporter Transporter subunit D transporter

ATP6V1 E1 Atpase H+ transporting V1 529 Channel or Transporter Transporter subunit E1 transporter

ATP6V1 E2 Atpase H+ transporting V1 90423 Channel or Transporter Transporter subunit E2 transporter

ATP6V1 F Atpase H+ transporting V1 9296 Channel or Transporter Transporter subunit F transporter

ATP6V1 G1 Atpase H+ transporting V1 9550 Channel or Transporter Transporter subunit G1 transporter

ATP6V1 G2 Atpase H+ transporting V1 534 Channel or Transporter Transporter subunit G2 transporter

ATP6V1 G3 Atpase H+ transporting V1 127124 Channel or Transporter Transporter subunit G3 transporter

ATP6V1 H Atpase H+ transporting V1 51606 Channel or Transporter Transporter subunit H transporter

ATP7A Atpase copper transporting 538 Channel or Transporter Transporter alpha transporter

ATP7B Atpase copper transporting 540 Channel or Transporter Transporter beta transporter

ATP8A1 Atpase phospholipid 10396 Channel or Transporter Transporter transporting 8A1 transporter

ATP8A2 Atpase phospholipid 51761 Channel or Transporter Transporter transporting 8A2 transporter

ATP8B1 Atpase phospholipid 5205 Channel or Transporter Transporter transporting 8B1 transporter

ATP8B2 Atpase phospholipid 57198 Channel or Transporter Transporter transporting 8B2 transporter

ATP8B3 Atpase phospholipid 148229 Channel or Transporter Transporter transporting 8B3 transporter

ATP8B4 Atpase phospholipid 79895 Channel or Transporter Transporter transporting 8B4 (putative) transporter

ATP9A Atpase phospholipid 10079 Channel or Transporter Transporter transporting 9A (putative) transporter

ATP9B Atpase phospholipid 374868 Channel or Transporter Transporter transporting 9B (putative) transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

DIRC2 Disrupted in renal 84925 Channel or Transporter Transporter carcinoma 2 transporter

FLVCR1 Feline leukemia virus 28982 Channel or Transporter Transporter subgroup C cellular receptor transporter

1

FLVCR2 Feline leukemia virus 55640 Channel or Transporter Transporter subgroup C cellular receptor transporter

family member 2

FXYD2 FXYD domain containing 486 Channel or Transporter Transporter ion transport regulator 2 transporter

HTL High L-leucine transport 3343 Channel or Transporter Transporter transporter

MFSD7 Major facilitator superfamily 84179 Channel or Transporter Transporter domain containing 7 transporter

MT-ATP6 Mitochondrially encoded 4508 Channel or Transporter Transporter

ATP synthase 6 transporter

MT-ATP8 Mitochondrially encoded 4509 Channel or Transporter Transporter

ATP synthase 8 transporter

MTCH1 Mitochondrial carrier 1 23787 Channel or Transporter Transporter transporter

MTCH2 Mitochondrial carrier 2 23788 Channel or Transporter Transporter transporter

NPC1 L1 NPC1 like intracellular 29881 Channel or Transporter Transporter cholesterol transporter 1 transporter

RHAG Rh-associated glycoprotein 6005 Channel or Transporter Transporter transporter

RHBG Rh family B glycoprotein 57127 Channel or Transporter Transporter

(gene/pseudogene) transporter

RHCG Rh family C glycoprotein 51458 Channel or Transporter Transporter transporter

SLC1 0A1 Solute carrier family 10 6554 Channel or Transporter Transporter member 1 transporter

SLC1 0A2 Solute carrier family 10 6555 Channel or Transporter Transporter member 2 transporter

SLC1 0A3 Solute carrier family 10 8273 Channel or Transporter Transporter member 3 transporter

SLC1 0A4 Solute carrier family 10 201780 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 4 transporter

SLC1 0A5 Solute carrier family 10 347051 Channel or Transporter Transporter member 5 transporter

SLC1 0A6 Solute carrier family 10 345274 Channel or Transporter Transporter member 6 transporter

SLC1 0A7 Solute carrier family 10 84068 Channel or Transporter Transporter member 7 transporter

SLC1 1 A1 Solute carrier family 1 1 6556 Channel or Transporter Transporter member 1 transporter

SLC1 1 A2 Solute carrier family 1 1 4891 Channel or Transporter Transporter member 2 transporter

SLC12A1 Solute carrier family 12 6557 Channel or Transporter Transporter member 1 transporter

SLC12A2 Solute carrier family 12 6558 Channel or Transporter Transporter member 2 transporter

SLC12A3 Solute carrier family 12 6559 Channel or Transporter Transporter member 3 transporter

SLC12A4 Solute carrier family 12 6560 Channel or Transporter Transporter member 4 transporter

SLC12A5 Solute carrier family 12 57468 Channel or Transporter Transporter member 5 transporter

SLC12A6 Solute carrier family 12 9990 Channel or Transporter Transporter member 6 transporter

SLC12A7 Solute carrier family 12 10723 Channel or Transporter Transporter member 7 transporter

SLC12A8 Solute carrier family 12 84561 Channel or Transporter Transporter member 8 transporter

SLC12A9 Solute carrier family 12 56996 Channel or Transporter Transporter member 9 transporter

SLC13A1 Solute carrier family 13 6561 Channel or Transporter Transporter member 1 transporter

SLC13A2 Solute carrier family 13 9058 Channel or Transporter Transporter member 2 transporter

SLC13A3 Solute carrier family 13 64849 Channel or Transporter Transporter member 3 transporter

SLC13A4 Solute carrier family 13 26266 Channel or Transporter Transporter member 4 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC13A5 Solute carrier family 13 2841 1 1 Channel or Transporter Transporter member 5 transporter

SLC14A1 Solute carrier family 14 6563 Channel or Transporter Transporter member 1 (Kidd blood transporter

group)

SLC14A2 Solute carrier family 14 8170 Channel or Transporter Transporter member 2 transporter

SLC1 5A1 Solute carrier family 15 6564 Channel or Transporter Transporter member 1 transporter

SLC1 5A2 Solute carrier family 15 6565 Channel or Transporter Transporter member 2 transporter

SLC1 5A3 Solute carrier family 15 51296 Channel or Transporter Transporter member 3 transporter

SLC1 5A4 Solute carrier family 15 121260 Channel or Transporter Transporter member 4 transporter

SLC1 6A1 Solute carrier family 16 6566 Channel or Transporter Transporter member 1 transporter

SLC1 6A10 Solute carrier family 16 1 17247 Channel or Transporter Transporter member 10 transporter

SLC1 6A1 1 Solute carrier family 16 162515 Channel or Transporter Transporter member 1 1 transporter

SLC1 6A12 Solute carrier family 16 387700 Channel or Transporter Transporter member 12 transporter

SLC1 6A13 Solute carrier family 16 201232 Channel or Transporter Transporter member 13 transporter

SLC1 6A14 Solute carrier family 16 151473 Channel or Transporter Transporter member 14 transporter

SLC1 6A2 Solute carrier family 16 6567 Channel or Transporter Transporter member 2 transporter

SLC1 6A3 Solute carrier family 16 9123 Channel or Transporter Transporter member 3 transporter

SLC1 6A4 Solute carrier family 16 9122 Channel or Transporter Transporter member 4 transporter

SLC1 6A5 Solute carrier family 16 9121 Channel or Transporter Transporter member 5 transporter

SLC1 6A6 Solute carrier family 16 9120 Channel or Transporter Transporter member 6 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC1 6A7 Solute carrier family 16 9194 Channel or Transporter Transporter member 7 transporter

SLC1 6A8 Solute carrier family 16 23539 Channel or Transporter Transporter member 8 transporter

SLC1 6A9 Solute carrier family 16 220963 Channel or Transporter Transporter member 9 transporter

SLC1 7A1 Solute carrier family 17 6568 Channel or Transporter Transporter member 1 transporter

SLC1 7A2 Solute carrier family 17 10246 Channel or Transporter Transporter member 2 transporter

SLC1 7A3 Solute carrier family 17 10786 Channel or Transporter Transporter member 3 transporter

SLC1 7A4 Solute carrier family 17 10050 Channel or Transporter Transporter member 4 transporter

SLC1 7A5 Solute carrier family 17 26503 Channel or Transporter Transporter member 5 transporter

SLC1 7A6 Solute carrier family 17 57084 Channel or Transporter Transporter member 6 transporter

SLC1 7A7 Solute carrier family 17 57030 Channel or Transporter Transporter member 7 transporter

SLC1 7A8 Solute carrier family 17 246213 Channel or Transporter Transporter member 8 transporter

SLC1 7A9 Solute carrier family 17 6391 0 Channel or Transporter Transporter member 9 transporter

SLC1 8A1 Solute carrier family 18 6570 Channel or Transporter Transporter member A1 transporter

SLC1 8A2 Solute carrier family 18 6571 Channel or Transporter Transporter member A2 transporter

SLC1 8A3 Solute carrier family 18 6572 Channel or Transporter Transporter member A3 transporter

SLC1 8B1 Solute carrier family 18 1 16843 Channel or Transporter Transporter member B1 transporter

SLC1 9A1 Solute carrier family 19 6573 Channel or Transporter Transporter member 1 transporter

SLC1 9A2 Solute carrier family 19 10560 Channel or Transporter Transporter member 2 transporter

SLC1 9A3 Solute carrier family 19 80704 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 3 transporter

SLC1 A1 Solute carrier family 1 6505 Channel or Transporter Transporter member 1 transporter

SLC1 A2 Solute carrier family 1 6506 Channel or Transporter Transporter member 2 transporter

SLC1 A3 Solute carrier family 1 6507 Channel or Transporter Transporter member 3 transporter

SLC1 A6 Solute carrier family 1 651 1 Channel or Transporter Transporter member 6 transporter

SLC1 A7 Solute carrier family 1 6512 Channel or Transporter Transporter member 7 transporter

SLC20A1 Solute carrier family 20 6574 Channel or Transporter Transporter member 1 transporter

SLC20A2 Solute carrier family 20 6575 Channel or Transporter Transporter member 2 transporter

SLC22A1 Solute carrier family 22 6580 Channel or Transporter Transporter member 1 transporter

SLC22A10 Solute carrier family 22 387775 Channel or Transporter Transporter member 10 transporter

SLC22A1 1 Solute carrier family 22 55867 Channel or Transporter Transporter member 1 1 transporter

SLC22A12 Solute carrier family 22 1 16085 Channel or Transporter Transporter member 12 transporter

SLC22A13 Solute carrier family 22 9390 Channel or Transporter Transporter member 13 transporter

SLC22A14 Solute carrier family 22 9389 Channel or Transporter Transporter member 14 transporter

SLC22A15 Solute carrier family 22 55356 Channel or Transporter Transporter member 15 transporter

SLC22A16 Solute carrier family 22 85413 Channel or Transporter Transporter member 16 transporter

SLC22A17 Solute carrier family 22 5131 0 Channel or Transporter Transporter member 17 transporter

SLC22A18 Solute carrier family 22 5002 Channel or Transporter Transporter member 18 transporter

SLC22A2 Solute carrier family 22 6582 Channel or Transporter Transporter member 2 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC22A20 Solute carrier family 22 440044 Channel or Transporter Transporter member 20 transporter

SLC22A23 Solute carrier family 22 63027 Channel or Transporter Transporter member 23 transporter

SLC22A24 Solute carrier family 22 283238 Channel or Transporter Transporter member 24 transporter

SLC22A25 Solute carrier family 22 387601 Channel or Transporter Transporter member 25 transporter

SLC22A3 Solute carrier family 22 6581 Channel or Transporter Transporter member 3 transporter

SLC22A31 Solute carrier family 22 146429 Channel or Transporter Transporter member 31 transporter

SLC22A4 Solute carrier family 22 6583 Channel or Transporter Transporter member 4 transporter

SLC22A5 Solute carrier family 22 6584 Channel or Transporter Transporter member 5 transporter

SLC22A6 Solute carrier family 22 9356 Channel or Transporter Transporter member 6 transporter

SLC22A7 Solute carrier family 22 10864 Channel or Transporter Transporter member 7 transporter

SLC22A8 Solute carrier family 22 9376 Channel or Transporter Transporter member 8 transporter

SLC22A9 Solute carrier family 22 1 14571 Channel or Transporter Transporter member 9 transporter

SLC23A1 Solute carrier family 23 9963 Channel or Transporter Transporter member 1 transporter

SLC23A2 Solute carrier family 23 9962 Channel or Transporter Transporter member 2 transporter

SLC23A3 Solute carrier family 23 151295 Channel or Transporter Transporter member 3 transporter

SLC23A4P Solute carrier family 23 641842 Channel or Transporter Transporter member 4, pseudogene transporter

SLC24A1 Solute carrier family 24 9187 Channel or Transporter Transporter member 1 transporter

SLC24A2 Solute carrier family 24 25769 Channel or Transporter Transporter member 2 transporter

SLC24A3 Solute carrier family 24 5741 9 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 3 transporter

SLC24A4 Solute carrier family 24 123041 Channel or Transporter Transporter member 4 transporter

SLC24A5 Solute carrier family 24 283652 Channel or Transporter Transporter member 5 transporter

SLC25A1 Solute carrier family 25 6576 Channel or Transporter Transporter member 1 transporter

SLC25A10 Solute carrier family 25 1468 Channel or Transporter Transporter member 10 transporter

SLC25A1 1 Solute carrier family 25 8402 Channel or Transporter Transporter member 1 1 transporter

SLC25A12 Solute carrier family 25 8604 Channel or Transporter Transporter member 12 transporter

SLC25A13 Solute carrier family 25 10165 Channel or Transporter Transporter member 13 transporter

SLC25A14 Solute carrier family 25 9016 Channel or Transporter Transporter member 14 transporter

SLC25A15 Solute carrier family 25 10166 Channel or Transporter Transporter member 15 transporter

SLC25A16 Solute carrier family 25 8034 Channel or Transporter Transporter member 16 transporter

SLC25A17 Solute carrier family 25 10478 Channel or Transporter Transporter member 17 transporter

SLC25A18 Solute carrier family 25 83733 Channel or Transporter Transporter member 18 transporter

SLC25A19 Solute carrier family 25 60386 Channel or Transporter Transporter member 19 transporter

SLC25A2 Solute carrier family 25 83884 Channel or Transporter Transporter member 2 transporter

SLC25A20 Solute carrier family 25 788 Channel or Transporter Transporter member 20 transporter

SLC25A21 Solute carrier family 25 89874 Channel or Transporter Transporter member 21 transporter

SLC25A22 Solute carrier family 25 79751 Channel or Transporter Transporter member 22 transporter

SLC25A23 Solute carrier family 25 79085 Channel or Transporter Transporter member 23 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC25A24 Solute carrier family 25 29957 Channel or Transporter Transporter member 24 transporter

SLC25A25 Solute carrier family 25 1 14789 Channel or Transporter Transporter member 25 transporter

SLC25A26 Solute carrier family 25 1 15286 Channel or Transporter Transporter member 26 transporter

SLC25A27 Solute carrier family 25 9481 Channel or Transporter Transporter member 27 transporter

SLC25A28 Solute carrier family 25 81894 Channel or Transporter Transporter member 28 transporter

SLC25A29 Solute carrier family 25 123096 Channel or Transporter Transporter member 29 transporter

SLC25A3 Solute carrier family 25 5250 Channel or Transporter Transporter member 3 transporter

SLC25A30 Solute carrier family 25 253512 Channel or Transporter Transporter member 30 transporter

SLC25A31 Solute carrier family 25 83447 Channel or Transporter Transporter member 31 transporter

SLC25A32 Solute carrier family 25 81034 Channel or Transporter Transporter member 32 transporter

SLC25A33 Solute carrier family 25 84275 Channel or Transporter Transporter member 33 transporter

SLC25A34 Solute carrier family 25 284723 Channel or Transporter Transporter member 34 transporter

SLC25A35 Solute carrier family 25 399512 Channel or Transporter Transporter member 35 transporter

SLC25A36 Solute carrier family 25 55186 Channel or Transporter Transporter member 36 transporter

SLC25A37 Solute carrier family 25 51312 Channel or Transporter Transporter member 37 transporter

SLC25A38 Solute carrier family 25 54977 Channel or Transporter Transporter member 38 transporter

SLC25A39 Solute carrier family 25 51629 Channel or Transporter Transporter member 39 transporter

SLC25A4 Solute carrier family 25 291 Channel or Transporter Transporter member 4 transporter

SLC25A40 Solute carrier family 25 55972 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 40 transporter

SLC25A41 Solute carrier family 25 284427 Channel or Transporter Transporter member 41 transporter

SLC25A42 Solute carrier family 25 284439 Channel or Transporter Transporter member 42 transporter

SLC25A43 Solute carrier family 25 203427 Channel or Transporter Transporter member 43 transporter

SLC25A44 Solute carrier family 25 9673 Channel or Transporter Transporter member 44 transporter

SLC25A45 Solute carrier family 25 283130 Channel or Transporter Transporter member 45 transporter

SLC25A46 Solute carrier family 25 91 137 Channel or Transporter Transporter member 46 transporter

SLC25A47 Solute carrier family 25 283600 Channel or Transporter Transporter member 47 transporter

SLC25A48 Solute carrier family 25 153328 Channel or Transporter Transporter member 48 transporter

SLC25A5 Solute carrier family 25 292 Channel or Transporter Transporter member 5 transporter

SLC25A51 Solute carrier family 25 92014 Channel or Transporter Transporter member 51 transporter

SLC25A52 Solute carrier family 25 147407 Channel or Transporter Transporter member 52 transporter

SLC25A53 Solute carrier family 25 401612 Channel or Transporter Transporter member 53 transporter

SLC25A6 Solute carrier family 25 293 Channel or Transporter Transporter member 6 transporter

SLC26A1 Solute carrier family 26 10861 Channel or Transporter Transporter member 1 transporter

SLC26A10 Solute carrier family 26 65012 Channel or Transporter Transporter member 10 transporter

SLC26A1 1 Solute carrier family 26 284129 Channel or Transporter Transporter member 1 1 transporter

SLC26A2 Solute carrier family 26 1836 Channel or Transporter Transporter member 2 transporter

SLC26A3 Solute carrier family 26 181 1 Channel or Transporter Transporter member 3 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC26A4 Solute carrier family 26 5172 Channel or Transporter Transporter member 4 transporter

SLC26A5 Solute carrier family 26 37561 1 Channel or Transporter Transporter member 5 transporter

SLC26A6 Solute carrier family 26 6501 0 Channel or Transporter Transporter member 6 transporter

SLC26A7 Solute carrier family 26 1 151 1 1 Channel or Transporter Transporter member 7 transporter

SLC26A8 Solute carrier family 26 1 16369 Channel or Transporter Transporter member 8 transporter

SLC26A9 Solute carrier family 26 1 15019 Channel or Transporter Transporter member 9 transporter

SLC27A1 Solute carrier family 27 376497 Channel or Transporter Transporter member 1 transporter

SLC27A2 Solute carrier family 27 1 1001 Channel or Transporter Transporter member 2 transporter

SLC27A3 Solute carrier family 27 1 1000 Channel or Transporter Transporter member 3 transporter

SLC27A4 Solute carrier family 27 10999 Channel or Transporter Transporter member 4 transporter

SLC27A5 Solute carrier family 27 10998 Channel or Transporter Transporter member 5 transporter

SLC27A6 Solute carrier family 27 28965 Channel or Transporter Transporter member 6 transporter

SLC28A1 Solute carrier family 28 9154 Channel or Transporter Transporter member 1 transporter

SLC28A2 Solute carrier family 28 9153 Channel or Transporter Transporter member 2 transporter

SLC28A3 Solute carrier family 28 64078 Channel or Transporter Transporter member 3 transporter

SLC29A1 Solute carrier family 29 2030 Channel or Transporter Transporter member 1 (Augustine blood transporter

group)

SLC29A2 Solute carrier family 29 3177 Channel or Transporter Transporter member 2 transporter

SLC29A3 Solute carrier family 29 5531 5 Channel or Transporter Transporter member 3 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC29A4 Solute carrier family 29 222962 Channel or Transporter Transporter member 4 transporter

SLC2A1 Solute carrier family 2 6513 Channel or Transporter Transporter member 1 transporter

SLC2A1 0 Solute carrier family 2 81031 Channel or Transporter Transporter member 10 transporter

SLC2A1 1 Solute carrier family 2 66035 Channel or Transporter Transporter member 1 1 transporter

SLC2A12 Solute carrier family 2 154091 Channel or Transporter Transporter member 12 transporter

SLC2A13 Solute carrier family 2 1 14134 Channel or Transporter Transporter member 13 transporter

SLC2A14 Solute carrier family 2 1441 95 Channel or Transporter Transporter member 14 transporter

SLC2A2 Solute carrier family 2 6514 Channel or Transporter Transporter member 2 transporter

SLC2A3 Solute carrier family 2 6515 Channel or Transporter Transporter member 3 transporter

SLC2A4 Solute carrier family 2 6517 Channel or Transporter Transporter member 4 transporter

SLC2A5 Solute carrier family 2 6518 Channel or Transporter Transporter member 5 transporter

SLC2A6 Solute carrier family 2 1 1 182 Channel or Transporter Transporter member 6 transporter

SLC2A7 Solute carrier family 2 1551 84 Channel or Transporter Transporter member 7 transporter

SLC2A8 Solute carrier family 2 29988 Channel or Transporter Transporter member 8 transporter

SLC2A9 Solute carrier family 2 56606 Channel or Transporter Transporter member 9 transporter

SLC30A1 Solute carrier family 30 7779 Channel or Transporter Transporter member 1 transporter

SLC30A10 Solute carrier family 30 55532 Channel or Transporter Transporter member 10 transporter

SLC30A2 Solute carrier family 30 7780 Channel or Transporter Transporter member 2 transporter

SLC30A3 Solute carrier family 30 7781 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 3 transporter

SLC30A4 Solute carrier family 30 7782 Channel or Transporter Transporter member 4 transporter

SLC30A5 Solute carrier family 30 64924 Channel or Transporter Transporter member 5 transporter

SLC30A6 Solute carrier family 30 55676 Channel or Transporter Transporter member 6 transporter

SLC30A7 Solute carrier family 30 148867 Channel or Transporter Transporter member 7 transporter

SLC30A8 Solute carrier family 30 169026 Channel or Transporter Transporter member 8 transporter

SLC30A9 Solute carrier family 30 10463 Channel or Transporter Transporter member 9 transporter

SLC31 A1 Solute carrier family 31 1317 Channel or Transporter Transporter member 1 transporter

SLC31 A2 Solute carrier family 31 1318 Channel or Transporter Transporter member 2 transporter

SLC32A1 Solute carrier family 32 140679 Channel or Transporter Transporter member 1 transporter

SLC33A1 Solute carrier family 33 9197 Channel or Transporter Transporter member 1 transporter

SLC34A1 Solute carrier family 34 6569 Channel or Transporter Transporter member 1 transporter

SLC34A2 Solute carrier family 34 10568 Channel or Transporter Transporter member 2 transporter

SLC34A3 Solute carrier family 34 142680 Channel or Transporter Transporter member 3 transporter

SLC35A1 Solute carrier family 35 10559 Channel or Transporter Transporter member A1 transporter

SLC35A2 Solute carrier family 35 7355 Channel or Transporter Transporter member A2 transporter

SLC35A3 Solute carrier family 35 23443 Channel or Transporter Transporter member A3 transporter

SLC35A4 Solute carrier family 35 1 13829 Channel or Transporter Transporter member A4 transporter

SLC35A5 Solute carrier family 35 55032 Channel or Transporter Transporter member A5 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC35B1 Solute carrier family 35 10237 Channel or Transporter Transporter member B1 transporter

SLC35B2 Solute carrier family 35 347734 Channel or Transporter Transporter member B2 transporter

SLC35B3 Solute carrier family 35 51000 Channel or Transporter Transporter member B3 transporter

SLC35B4 Solute carrier family 35 84912 Channel or Transporter Transporter member B4 transporter

SLC35C1 Solute carrier family 35 55343 Channel or Transporter Transporter member C1 transporter

SLC35C2 Solute carrier family 35 51006 Channel or Transporter Transporter member C2 transporter

SLC35D1 Solute carrier family 35 23169 Channel or Transporter Transporter member D1 transporter

SLC35D2 Solute carrier family 35 1 1046 Channel or Transporter Transporter member D2 transporter

SLC35D3 Solute carrier family 35 340146 Channel or Transporter Transporter member D3 transporter

SLC35E1 Solute carrier family 35 79939 Channel or Transporter Transporter member E1 transporter

SLC35E2 Solute carrier family 35 9906 Channel or Transporter Transporter member E2 transporter

SLC35E2B Solute carrier family 35 728661 Channel or Transporter Transporter member E2B transporter

SLC35E3 Solute carrier family 35 55508 Channel or Transporter Transporter member E3 transporter

SLC35E4 Solute carrier family 35 339665 Channel or Transporter Transporter member E4 transporter

SLC35F1 Solute carrier family 35 222553 Channel or Transporter Transporter member F1 transporter

SLC35F2 Solute carrier family 35 54733 Channel or Transporter Transporter member F2 transporter

SLC35F3 Solute carrier family 35 148641 Channel or Transporter Transporter member F3 transporter

SLC35F4 Solute carrier family 35 341880 Channel or Transporter Transporter member F4 transporter

SLC35F5 Solute carrier family 35 80255 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member F5 transporter

SLC35F6 Solute carrier family 35 54978 Channel or Transporter Transporter member F6 transporter

SLC35G1 Solute carrier family 35 159371 Channel or Transporter Transporter member G1 transporter

SLC35G2 Solute carrier family 35 80723 Channel or Transporter Transporter member G2 transporter

SLC35G3 Solute carrier family 35 146861 Channel or Transporter Transporter member G3 transporter

SLC35G4 Solute carrier family 35 646000 Channel or Transporter Transporter member G4 transporter

SLC35G5 Solute carrier family 35 83650 Channel or Transporter Transporter member G5 transporter

SLC35G6 Solute carrier family 35 643664 Channel or Transporter Transporter member G6 transporter

SLC36A1 Solute carrier family 36 206358 Channel or Transporter Transporter member 1 transporter

SLC36A2 Solute carrier family 36 153201 Channel or Transporter Transporter member 2 transporter

SLC36A3 Solute carrier family 36 285641 Channel or Transporter Transporter member 3 transporter

SLC36A4 Solute carrier family 36 1201 03 Channel or Transporter Transporter member 4 transporter

SLC37A1 Solute carrier family 37 54020 Channel or Transporter Transporter member 1 transporter

SLC37A2 Solute carrier family 37 219855 Channel or Transporter Transporter member 2 transporter

SLC37A3 Solute carrier family 37 84255 Channel or Transporter Transporter member 3 transporter

SLC37A4 Solute carrier family 37 2542 Channel or Transporter Transporter member 4 transporter

SLC38A1 Solute carrier family 38 81539 Channel or Transporter Transporter member 1 transporter

SLC38A10 Solute carrier family 38 124565 Channel or Transporter Transporter member 10 transporter

SLC38A1 1 Solute carrier family 38 151258 Channel or Transporter Transporter member 1 1 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC38A2 Solute carrier family 38 54407 Channel or Transporter Transporter member 2 transporter

SLC38A3 Solute carrier family 38 10991 Channel or Transporter Transporter member 3 transporter

SLC38A4 Solute carrier family 38 55089 Channel or Transporter Transporter member 4 transporter

SLC38A5 Solute carrier family 38 92745 Channel or Transporter Transporter member 5 transporter

SLC38A6 Solute carrier family 38 145389 Channel or Transporter Transporter member 6 transporter

SLC38A7 Solute carrier family 38 55238 Channel or Transporter Transporter member 7 transporter

SLC38A8 Solute carrier family 38 1461 67 Channel or Transporter Transporter member 8 transporter

SLC38A9 Solute carrier family 38 153129 Channel or Transporter Transporter member 9 transporter

SLC39A1 Solute carrier family 39 27173 Channel or Transporter Transporter member 1 transporter

SLC39A10 Solute carrier family 39 57181 Channel or Transporter Transporter member 10 transporter

SLC39A1 1 Solute carrier family 39 201266 Channel or Transporter Transporter member 1 1 transporter

SLC39A12 Solute carrier family 39 221074 Channel or Transporter Transporter member 12 transporter

SLC39A13 Solute carrier family 39 91252 Channel or Transporter Transporter member 13 transporter

SLC39A14 Solute carrier family 39 2351 6 Channel or Transporter Transporter member 14 transporter

SLC39A2 Solute carrier family 39 29986 Channel or Transporter Transporter member 2 transporter

SLC39A3 Solute carrier family 39 29985 Channel or Transporter Transporter member 3 transporter

SLC39A4 Solute carrier family 39 55630 Channel or Transporter Transporter member 4 transporter

SLC39A5 Solute carrier family 39 283375 Channel or Transporter Transporter member 5 transporter

SLC39A6 Solute carrier family 39 25800 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 6 transporter

SLC39A7 Solute carrier family 39 7922 Channel or Transporter Transporter member 7 transporter

SLC39A8 Solute carrier family 39 641 1 6 Channel or Transporter Transporter member 8 transporter

SLC39A9 Solute carrier family 39 55334 Channel or Transporter Transporter member 9 transporter

SLC3A1 Solute carrier family 3 6519 Channel or Transporter Transporter member 1 transporter

SLC3A2 Solute carrier family 3 6520 Channel or Transporter Transporter member 2 transporter

SLC40A1 Solute carrier family 40 30061 Channel or Transporter Transporter member 1 transporter

SLC41 A1 Solute carrier family 41 254428 Channel or Transporter Transporter member 1 transporter

SLC41 A2 Solute carrier family 41 84102 Channel or Transporter Transporter member 2 transporter

SLC41 A3 Solute carrier family 41 54946 Channel or Transporter Transporter member 3 transporter

SLC43A1 Solute carrier family 43 8501 Channel or Transporter Transporter member 1 transporter

SLC43A2 Solute carrier family 43 124935 Channel or Transporter Transporter member 2 transporter

SLC43A3 Solute carrier family 43 2901 5 Channel or Transporter Transporter member 3 transporter

SLC44A1 Solute carrier family 44 23446 Channel or Transporter Transporter member 1 transporter

SLC44A2 Solute carrier family 44 57153 Channel or Transporter Transporter member 2 transporter

SLC44A3 Solute carrier family 44 126969 Channel or Transporter Transporter member 3 transporter

SLC44A4 Solute carrier family 44 80736 Channel or Transporter Transporter member 4 transporter

SLC44A5 Solute carrier family 44 204962 Channel or Transporter Transporter member 5 transporter

SLC45A1 Solute carrier family 45 50651 Channel or Transporter Transporter member 1 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC45A2 Solute carrier family 45 51 151 Channel or Transporter Transporter member 2 transporter

SLC45A3 Solute carrier family 45 85414 Channel or Transporter Transporter member 3 transporter

SLC45A4 Solute carrier family 45 5721 0 Channel or Transporter Transporter member 4 transporter

SLC46A1 Solute carrier family 46 1 13235 Channel or Transporter Transporter member 1 transporter

SLC46A2 Solute carrier family 46 57864 Channel or Transporter Transporter member 2 transporter

SLC46A3 Solute carrier family 46 283537 Channel or Transporter Transporter member 3 transporter

SLC47A1 Solute carrier family 47 55244 Channel or Transporter Transporter member 1 transporter

SLC47A2 Solute carrier family 47 146802 Channel or Transporter Transporter member 2 transporter

SLC48A1 Solute carrier family 48 55652 Channel or Transporter Transporter member 1 transporter

SLC4A1 Solute carrier family 4 6521 Channel or Transporter Transporter member 1 transporter

SLC4A1 0 Solute carrier family 4 57282 Channel or Transporter Transporter member 10 transporter

SLC4A1 1 Solute carrier family 4 83959 Channel or Transporter Transporter member 1 1 transporter

SLC4A2 Solute carrier family 4 6522 Channel or Transporter Transporter member 2 transporter

SLC4A3 Solute carrier family 4 6508 Channel or Transporter Transporter member 3 transporter

SLC4A4 Solute carrier family 4 8671 Channel or Transporter Transporter member 4 transporter

SLC4A5 Solute carrier family 4 57835 Channel or Transporter Transporter member 5 transporter

SLC4A7 Solute carrier family 4 9497 Channel or Transporter Transporter member 7 transporter

SLC4A8 Solute carrier family 4 9498 Channel or Transporter Transporter member 8 transporter

SLC4A9 Solute carrier family 4 83697 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 9 transporter

SLC50A1 Solute carrier family 50 55974 Channel or Transporter Transporter member 1 transporter

SLC51 A Solute carrier family 51 200931 Channel or Transporter Transporter alpha subunit transporter

SLC51 B Solute carrier family 51 beta 123264 Channel or Transporter Transporter subunit transporter

SLC52A1 Solute carrier family 52 55065 Channel or Transporter Transporter member 1 transporter

SLC52A2 Solute carrier family 52 79581 Channel or Transporter Transporter member 2 transporter

SLC52A3 Solute carrier family 52 1 13278 Channel or Transporter Transporter member 3 transporter

SLC5A1 Solute carrier family 5 6523 Channel or Transporter Transporter member 1 transporter

SLC5A1 0 Solute carrier family 5 125206 Channel or Transporter Transporter member 10 transporter

SLC5A1 1 Solute carrier family 5 1 15584 Channel or Transporter Transporter member 1 1 transporter

SLC5A12 Solute carrier family 5 159963 Channel or Transporter Transporter member 12 transporter

SLC5A2 Solute carrier family 5 6524 Channel or Transporter Transporter member 2 transporter

SLC5A3 Solute carrier family 5 6526 Channel or Transporter Transporter member 3 transporter

SLC5A4 Solute carrier family 5 6527 Channel or Transporter Transporter member 4 transporter

SLC5A5 Solute carrier family 5 6528 Channel or Transporter Transporter member 5 transporter

SLC5A6 Solute carrier family 5 8884 Channel or Transporter Transporter member 6 transporter

SLC5A7 Solute carrier family 5 60482 Channel or Transporter Transporter member 7 transporter

SLC5A8 Solute carrier family 5 160728 Channel or Transporter Transporter member 8 transporter

SLC5A9 Solute carrier family 5 200010 Channel or Transporter Transporter member 9 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC6A1 Solute carrier family 6 6529 Channel or Transporter Transporter member 1 transporter

SLC6A1 0P Solute carrier family 6 386757 Channel or Transporter Transporter member 10, pseudogene transporter

SLC6A1 0PB Solute carrier family 6 653562 Channel or Transporter Transporter member 8 pseudogene transporter

SLC6A1 1 Solute carrier family 6 6538 Channel or Transporter Transporter member 1 1 transporter

SLC6A12 Solute carrier family 6 6539 Channel or Transporter Transporter member 12 transporter

SLC6A13 Solute carrier family 6 6540 Channel or Transporter Transporter member 13 transporter

SLC6A14 Solute carrier family 6 1 1254 Channel or Transporter Transporter member 14 transporter

SLC6A1 5 Solute carrier family 6 551 1 7 Channel or Transporter Transporter member 15 transporter

SLC6A1 6 Solute carrier family 6 28968 Channel or Transporter Transporter member 16 transporter

SLC6A1 7 Solute carrier family 6 388662 Channel or Transporter Transporter member 17 transporter

SLC6A1 8 Solute carrier family 6 348932 Channel or Transporter Transporter member 18 transporter

SLC6A1 9 Solute carrier family 6 340024 Channel or Transporter Transporter member 19 transporter

SLC6A2 Solute carrier family 6 6530 Channel or Transporter Transporter member 2 transporter

SLC6A20 Solute carrier family 6 5471 6 Channel or Transporter Transporter member 20 transporter

SLC6A21 P Solute carrier family 6 652969 Channel or Transporter Transporter member 21 , pseudogene transporter

SLC6A3 Solute carrier family 6 6531 Channel or Transporter Transporter member 3 transporter

SLC6A4 Solute carrier family 6 6532 Channel or Transporter Transporter member 4 transporter

SLC6A5 Solute carrier family 6 9152 Channel or Transporter Transporter member 5 transporter

SLC6A6 Solute carrier family 6 6533 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 6 transporter

SLC6A7 Solute carrier family 6 6534 Channel or Transporter Transporter member 7 transporter

SLC6A8 Solute carrier family 6 6535 Channel or Transporter Transporter member 8 transporter

SLC6A9 Solute carrier family 6 6536 Channel or Transporter Transporter member 9 transporter

SLC7A1 Solute carrier family 7 6541 Channel or Transporter Transporter member 1 transporter

SLC7A1 0 Solute carrier family 7 56301 Channel or Transporter Transporter member 10 transporter

SLC7A1 1 Solute carrier family 7 23657 Channel or Transporter Transporter member 1 1 transporter

SLC7A13 Solute carrier family 7 157724 Channel or Transporter Transporter member 13 transporter

SLC7A14 Solute carrier family 7 57709 Channel or Transporter Transporter member 14 transporter

SLC7A2 Solute carrier family 7 6542 Channel or Transporter Transporter member 2 transporter

SLC7A3 Solute carrier family 7 84889 Channel or Transporter Transporter member 3 transporter

SLC7A4 Solute carrier family 7 6545 Channel or Transporter Transporter member 4 transporter

SLC7A5 Solute carrier family 7 8140 Channel or Transporter Transporter member 5 transporter

SLC7A6 Solute carrier family 7 9057 Channel or Transporter Transporter member 6 transporter

SLC7A7 Solute carrier family 7 9056 Channel or Transporter Transporter member 7 transporter

SLC7A8 Solute carrier family 7 23428 Channel or Transporter Transporter member 8 transporter

SLC7A9 Solute carrier family 7 1 1 136 Channel or Transporter Transporter member 9 transporter

SLC8A1 Solute carrier family 8 6546 Channel or Transporter Transporter member A1 transporter

SLC8A2 Solute carrier family 8 6543 Channel or Transporter Transporter member A2 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

SLC8A3 Solute carrier family 8 6547 Channel or Transporter Transporter member A3 transporter

SLC8B1 Solute carrier family 8 80024 Channel or Transporter Transporter member B1 transporter

SLC9A1 Solute carrier family 9 6548 Channel or Transporter Transporter member A1 transporter

SLC9A2 Solute carrier family 9 6549 Channel or Transporter Transporter member A2 transporter

SLC9A3 Solute carrier family 9 6550 Channel or Transporter Transporter member A3 transporter

SLC9A4 Solute carrier family 9 389015 Channel or Transporter Transporter member A4 transporter

SLC9A5 Solute carrier family 9 6553 Channel or Transporter Transporter member A5 transporter

SLC9A6 Solute carrier family 9 10479 Channel or Transporter Transporter member A6 transporter

SLC9A7 Solute carrier family 9 84679 Channel or Transporter Transporter member A7 transporter

SLC9A8 Solute carrier family 9 2331 5 Channel or Transporter Transporter member A8 transporter

SLC9A9 Solute carrier family 9 2851 95 Channel or Transporter Transporter member A9 transporter

SLC9B1 Solute carrier family 9 1501 59 Channel or Transporter Transporter member B1 transporter

SLC9B2 Solute carrier family 9 133308 Channel or Transporter Transporter member B2 transporter

SLC9C1 Solute carrier family 9 285335 Channel or Transporter Transporter member C1 transporter

SLC9C2 Solute carrier family 9 284525 Channel or Transporter Transporter member C2 (putative) transporter

SLC01 A2 Solute carrier organic anion 6579 Channel or Transporter Transporter transporter family member transporter

1 A2

SLC01 B1 Solute carrier organic anion 10599 Channel or Transporter Transporter transporter family member transporter

1 B1

SLC01 B3 Solute carrier organic anion 28234 Channel or Transporter Transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type transporter family member transporter

1 B3

SLC01 C1 Solute carrier organic anion 5391 9 Channel or Transporter Transporter transporter family member transporter

1 C1

SLC02A1 Solute carrier organic anion 6578 Channel or Transporter Transporter transporter family member transporter

2A1

SLC02B1 Solute carrier organic anion 1 1309 Channel or Transporter Transporter transporter family member transporter

2B1

SLC03A1 Solute carrier organic anion 28232 Channel or Transporter Transporter transporter family member transporter

3A1

SLC04A1 Solute carrier organic anion 28231 Channel or Transporter Transporter transporter family member transporter

4A1

SLC04C1 Solute carrier organic anion 3531 89 Channel or Transporter Transporter transporter family member transporter

4C1

SLC05A1 Solute carrier organic anion 81796 Channel or Transporter Transporter transporter family member transporter

5A1

SLC06A1 Solute carrier organic anion 133482 Channel or Transporter Transporter transporter family member transporter

6A1

TCIRG1 T-cell immune regulator 1 , 10312 Channel or Transporter Transporter atpase H+ transporting V0 transporter

subunit a3

UCP1 Uncoupling protein 1 7350 Channel or Transporter Transporter transporter

UCP2 Uncoupling protein 2 7351 Channel or Transporter Transporter transporter

UCP3 Uncoupling protein 3 7352 Channel or Transporter Transporter transporter

CACNA1 A Calcium voltage-gated 773 Channel or Channel Vgic

channel subunit alphal A transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

CACNA1 B Calcium voltage-gated 774 Channel or Channel Vgic channel subunit alphal B transporter

CACNA1 C Calcium voltage-gated 775 Channel or Channel Vgic channel subunit alphal C transporter

CACNA1 D Calcium voltage-gated 776 Channel or Channel Vgic channel subunit alphal D transporter

CACNA1 E Calcium voltage-gated 777 Channel or Channel Vgic channel subunit alphal E transporter

CACNA1 F Calcium voltage-gated 778 Channel or Channel Vgic channel subunit alphal F transporter

CACNA1 G Calcium voltage-gated 8913 Channel or Channel Vgic channel subunit alphal G transporter

CACNA1 H Calcium voltage-gated 8912 Channel or Channel Vgic channel subunit alphal H transporter

CACNA1 1 Calcium voltage-gated 891 1 Channel or Channel Vgic channel subunit alphal 1 transporter

CACNA1 S Calcium voltage-gated 779 Channel or Channel Vgic channel subunit alphal S transporter

CACNB1 Calcium voltage-gated 782 Channel or Channel Vgic channel auxiliary subunit transporter

beta 1

CACNB2 Calcium voltage-gated 783 Channel or Channel Vgic channel auxiliary subunit transporter

beta 2

CACNB4 Calcium voltage-gated 785 Channel or Channel Vgic channel auxiliary subunit transporter

beta 4

CATSPER1 Cation channel sperm 1 17144 Channel or Channel Vgic associated 1 transporter

CATSPER2 Cation channel sperm 1 171 55 Channel or Channel Vgic associated 2 transporter

CATSPER3 Cation channel sperm 347732 Channel or Channel Vgic associated 3 transporter

CATSPER4 Cation channel sperm 378807 Channel or Channel Vgic associated 4 transporter

CNGA1 Cyclic nucleotide gated 1259 Channel or Channel Vgic channel alpha 1 transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

CNGA2 Cyclic nucleotide gated 1260 Channel or Channel Vgic channel alpha 2 transporter

CNGA3 Cyclic nucleotide gated 1261 Channel or Channel Vgic channel alpha 3 transporter

CNGA4 Cyclic nucleotide gated 1262 Channel or Channel Vgic channel alpha 4 transporter

CNGB1 Cyclic nucleotide gated 1258 Channel or Channel Vgic channel beta 1 transporter

CNGB3 Cyclic nucleotide gated 54714 Channel or Channel Vgic channel beta 3 transporter

HCN1 Hyperpolarization activated 348980 Channel or Channel Vgic cyclic nucleotide gated transporter

potassium channel 1

HCN2 Hyperpolarization activated 610 Channel or Channel Vgic cyclic nucleotide gated transporter

potassium channel 2

HCN3 Hyperpolarization activated 57657 Channel or Channel Vgic cyclic nucleotide gated transporter

potassium channel 3

HCN4 Hyperpolarization activated 10021 Channel or Channel Vgic cyclic nucleotide gated transporter

potassium channel 4

HVCN1 Hydrogen voltage gated 84329 Channel or Channel Vgic channel 1 transporter

KCNA1 Potassium voltage-gated 3736 Channel or Channel Vgic channel subfamily A transporter

member 1

KCNA10 Potassium voltage-gated 3744 Channel or Channel Vgic channel subfamily A transporter

member 10

KCNA2 Potassium voltage-gated 3737 Channel or Channel Vgic channel subfamily A transporter

member 2

KCNA3 Potassium voltage-gated 3738 Channel or Channel Vgic channel subfamily A transporter

member 3

KCNA4 Potassium voltage-gated 3739 Channel or Channel Vgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type channel subfamily A transporter

member 4

KCNA5 Potassium voltage-gated 3741 Channel or Channel Vgic channel subfamily A transporter

member 5

KCNA6 Potassium voltage-gated 3742 Channel or Channel Vgic channel subfamily A transporter

member 6

KCNA7 Potassium voltage-gated 3743 Channel or Channel Vgic channel subfamily A transporter

member 7

KCNAB1 Potassium voltage-gated 7881 Channel or Channel Vgic channel subfamily A transporter

member regulatory beta

subunit 1

KCNAB2 Potassium voltage-gated 8514 Channel or Channel Vgic channel subfamily A transporter

regulatory beta subunit 2

KCNB1 Potassium voltage-gated 3745 Channel or Channel Vgic channel subfamily B transporter

member 1

KCNB2 Potassium voltage-gated 9312 Channel or Channel Vgic channel subfamily B transporter

member 2

KCNC1 Potassium voltage-gated 3746 Channel or Channel Vgic channel subfamily C transporter

member 1

KCNC2 Potassium voltage-gated 3747 Channel or Channel Vgic channel subfamily C transporter

member 2

KCNC3 Potassium voltage-gated 3748 Channel or Channel Vgic channel subfamily C transporter

member 3

KCNC4 Potassium voltage-gated 3749 Channel or Channel Vgic channel subfamily C transporter

member 4

KCND1 Potassium voltage-gated 3750 Channel or Channel Vgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type channel subfamily D transporter

member 1

KCND2 Potassium voltage-gated 3751 Channel or Channel Vgic channel subfamily D transporter

member 2

KCND3 Potassium voltage-gated 3752 Channel or Channel Vgic channel subfamily D transporter

member 3

KCNE2 Potassium voltage-gated 9992 Channel or Channel Vgic channel subfamily E transporter

regulatory subunit 2

KCNE3 Potassium voltage-gated 10008 Channel or Channel Vgic channel subfamily E transporter

regulatory subunit 3

KCNE4 Potassium voltage-gated 23704 Channel or Channel Vgic channel subfamily E transporter

regulatory subunit 4

KCNF1 Potassium voltage-gated 3754 Channel or Channel Vgic channel modifier subfamily transporter

F member 1

KCNG1 Potassium voltage-gated 3755 Channel or Channel Vgic channel modifier subfamily transporter

G member 1

KCNG2 Potassium voltage-gated 26251 Channel or Channel Vgic channel modifier subfamily transporter

G member 2

KCNG3 Potassium voltage-gated 170850 Channel or Channel Vgic channel modifier subfamily transporter

G member 3

KCNG4 Potassium voltage-gated 93107 Channel or Channel Vgic channel modifier subfamily transporter

G member 4

KCNH1 Potassium voltage-gated 3756 Channel or Channel Vgic channel subfamily H transporter

member 1

KCNH2 Potassium voltage-gated 3757 Channel or Channel Vgic channel subfamily H transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type member 2

KCNH3 Potassium voltage-gated 2341 6 Channel or Channel Vgic channel subfamily H transporter

member 3

KCNH4 Potassium voltage-gated 2341 5 Channel or Channel Vgic channel subfamily H transporter

member 4

KCNH5 Potassium voltage-gated 27133 Channel or Channel Vgic channel subfamily H transporter

member 5

KCNH6 Potassium voltage-gated 81033 Channel or Channel Vgic channel subfamily H transporter

member 6

KCNH7 Potassium voltage-gated 90134 Channel or Channel Vgic channel subfamily H transporter

member 7

KCNH8 Potassium voltage-gated 131096 Channel or Channel Vgic channel subfamily H transporter

member 8

KCNJ1 Potassium voltage-gated 3758 Channel or Channel Vgic channel subfamily J transporter

member 1

KCNJ10 Potassium voltage-gated 3766 Channel or Channel Vgic channel subfamily J transporter

member 10

KCNJ1 1 Potassium voltage-gated 3767 Channel or Channel Vgic channel subfamily J transporter

member 1 1

KCNJ12 Potassium voltage-gated 3768 Channel or Channel Vgic channel subfamily J transporter

member 12

KCNJ13 Potassium voltage-gated 3769 Channel or Channel Vgic channel subfamily J transporter

member 13

KCNJ14 Potassium voltage-gated 3770 Channel or Channel Vgic channel subfamily J transporter

member 14 Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

KCNJ15 Potassium voltage-gated 3772 Channel or Channel Vgic channel subfamily J transporter

member 15

KCNJ16 Potassium voltage-gated 3773 Channel or Channel Vgic channel subfamily J transporter

member 16

KCNJ2 Potassium voltage-gated 3759 Channel or Channel Vgic channel subfamily J transporter

member 2

KCNJ3 Potassium voltage-gated 3760 Channel or Channel Vgic channel subfamily J transporter

member 3

KCNJ4 Potassium voltage-gated 3761 Channel or Channel Vgic channel subfamily J transporter

member 4

KCNJ5 Potassium voltage-gated 3762 Channel or Channel Vgic channel subfamily J transporter

member 5

KCNJ6 Potassium voltage-gated 3763 Channel or Channel Vgic channel subfamily J transporter

member 6

KCNJ8 Potassium voltage-gated 3764 Channel or Channel Vgic channel subfamily J transporter

member 8

KCNJ9 Potassium voltage-gated 3765 Channel or Channel Vgic channel subfamily J transporter

member 9

KCNK1 Potassium two pore domain 3775 Channel or Channel Vgic channel subfamily K transporter

member 1

KCNK10 Potassium two pore domain 54207 Channel or Channel Vgic channel subfamily K transporter

member 10

KCNK12 Potassium two pore domain 56660 Channel or Channel Vgic channel subfamily K transporter

member 12

KCNK13 Potassium two pore domain 56659 Channel or Channel Vgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type channel subfamily K transporter

member 13

KCNK15 Potassium two pore domain 60598 Channel or Channel Vgic channel subfamily K transporter

member 15

KCNK16 Potassium two pore domain 83795 Channel or Channel Vgic channel subfamily K transporter

member 16

KCNK17 Potassium two pore domain 89822 Channel or Channel Vgic channel subfamily K transporter

member 17

KCNK18 Potassium two pore domain 338567 Channel or Channel Vgic channel subfamily K transporter

member 18

KCNK2 Potassium two pore domain 3776 Channel or Channel Vgic channel subfamily K transporter

member 2

KCNK3 Potassium two pore domain 3777 Channel or Channel Vgic channel subfamily K transporter

member 3

KCNK4 Potassium two pore domain 50801 Channel or Channel Vgic channel subfamily K transporter

member 4

KCNK5 Potassium two pore domain 8645 Channel or Channel Vgic channel subfamily K transporter

member 5

KCNK6 Potassium two pore domain 9424 Channel or Channel Vgic channel subfamily K transporter

member 6

KCNK7 Potassium two pore domain 10089 Channel or Channel Vgic channel subfamily K transporter

member 7

KCNK9 Potassium two pore domain 51305 Channel or Channel Vgic channel subfamily K transporter

member 9

KCNMA1 Potassium calcium- 3778 Channel or Channel Vgic activated channel subfamily transporter Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

M alpha 1

KCNN1 Potassium calcium- 3780 Channel or Channel Vgic activated channel subfamily transporter

N member 1

KCNN2 Potassium calcium- 3781 Channel or Channel Vgic activated channel subfamily transporter

N member 2

KCNN3 Potassium calcium- 3782 Channel or Channel Vgic activated channel subfamily transporter

N member 3

KCNN4 Potassium calcium- 3783 Channel or Channel Vgic activated channel subfamily transporter

N member 4

KCNQ1 Potassium voltage-gated 3784 Channel or Channel Vgic channel subfamily Q transporter

member 1

KCNQ2 Potassium voltage-gated 3785 Channel or Channel Vgic channel subfamily Q transporter

member 2

KCNQ3 Potassium voltage-gated 3786 Channel or Channel Vgic channel subfamily Q transporter

member 3

KCNQ4 Potassium voltage-gated 9132 Channel or Channel Vgic channel subfamily Q transporter

member 4

KCNQ5 Potassium voltage-gated 56479 Channel or Channel Vgic channel subfamily Q transporter

member 5

KCNS1 Potassium voltage-gated 3787 Channel or Channel Vgic channel modifier subfamily transporter

S member 1

KCNS2 Potassium voltage-gated 3788 Channel or Channel Vgic channel modifier subfamily transporter

S member 2

KCNS3 Potassium voltage-gated 3790 Channel or Channel Vgic channel modifier subfamily transporter

S member 3 Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

KCNT1 Potassium sodium-activated 57582 Channel or Channel Vgic channel subfamily T transporter

member 1

KCNT2 Potassium sodium-activated 343450 Channel or Channel Vgic channel subfamily T transporter

member 2

KCNU1 Potassium calcium- 157855 Channel or Channel Vgic activated channel subfamily transporter

U member 1

KCNV1 Potassium voltage-gated 27012 Channel or Channel Vgic channel modifier subfamily transporter

V member 1

KCNV2 Potassium voltage-gated 169522 Channel or Channel Vgic channel modifier subfamily transporter

V member 2

MCOLN1 Mucolipin 1 57192 Channel or Channel Vgic transporter

MCOLN2 Mucolipin 2 255231 Channel or Channel Vgic transporter

MCOLN3 Mucolipin 3 55283 Channel or Channel Vgic transporter

PKD2 Polycystin 2, transient 531 1 Channel or Channel Vgic receptor potential cation transporter

channel

PKD2L1 Polycystin 2 like 1 , transient 9033 Channel or Channel Vgic receptor potential cation transporter

channel

PKD2L2 Polycystin 2 like 2, transient 27039 Channel or Channel Vgic receptor potential cation transporter

channel

RYR1 Ryanodine receptor 1 6261 Channel or Channel Vgic transporter

RYR2 Ryanodine receptor 2 6262 Channel or Channel Vgic transporter

RYR3 Ryanodine receptor 3 6263 Channel or Channel Vgic transporter

SCN1 0A Sodium voltage-gated 6336 Channel or Channel Vgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type channel alpha subunit 1 0 transporter

SCN1 1 A Sodium voltage-gated 1 1280 Channel or Channel Vgic channel alpha subunit 1 1 transporter

SCN1 A Sodium voltage-gated 6323 Channel or Channel Vgic channel alpha subunit 1 transporter

SCN1 B Sodium voltage-gated 6324 Channel or Channel Vgic channel beta subunit 1 transporter

SCN2A Sodium voltage-gated 6326 Channel or Channel Vgic channel alpha subunit 2 transporter

SCN2B Sodium voltage-gated 6327 Channel or Channel Vgic channel beta subunit 2 transporter

SCN3A Sodium voltage-gated 6328 Channel or Channel Vgic channel alpha subunit 3 transporter

SCN3B Sodium voltage-gated 55800 Channel or Channel Vgic channel beta subunit 3 transporter

SCN4A Sodium voltage-gated 6329 Channel or Channel Vgic channel alpha subunit 4 transporter

SCN4B Sodium voltage-gated 6330 Channel or Channel Vgic channel beta subunit 4 transporter

SCN5A Sodium voltage-gated 6331 Channel or Channel Vgic channel alpha subunit 5 transporter

SCN7A Sodium voltage-gated 6332 Channel or Channel Vgic channel alpha subunit 7 transporter

SCN8A Sodium voltage-gated 6334 Channel or Channel Vgic channel alpha subunit 8 transporter

SCN9A Sodium voltage-gated 6335 Channel or Channel Vgic channel alpha subunit 9 transporter

TPCN1 Two pore segment channel 53373 Channel or Channel Vgic

1 transporter

TPCN2 Two pore segment channel 219931 Channel or Channel Vgic

2 transporter

TRPA1 Transient receptor potential 8989 Channel or Channel Vgic cation channel subfamily A transporter

member 1

TRPC1 Transient receptor potential 7220 Channel or Channel Vgic cation channel subfamily C transporter

member 1 Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type

TRPC2 Transient receptor potential 7221 Channel or Channel Vgic cation channel subfamily C transporter

member 2, pseudogene

TRPC3 Transient receptor potential 7222 Channel or Channel Vgic cation channel subfamily C transporter

member 3

TRPC4 Transient receptor potential 7223 Channel or Channel Vgic cation channel subfamily C transporter

member 4

TRPC5 Transient receptor potential 7224 Channel or Channel Vgic cation channel subfamily C transporter

member 5

TRPC6 Transient receptor potential 7225 Channel or Channel Vgic cation channel subfamily C transporter

member 6

TRPC7 Transient receptor potential 571 13 Channel or Channel Vgic cation channel subfamily C transporter

member 7

TRPM1 Transient receptor potential 4308 Channel or Channel Vgic cation channel subfamily M transporter

member 1

TRPM2 Transient receptor potential 7226 Channel or Channel Vgic cation channel subfamily M transporter

member 2

TRPM3 Transient receptor potential 80036 Channel or Channel Vgic cation channel subfamily M transporter

member 3

TRPM4 Transient receptor potential 54795 Channel or Channel Vgic cation channel subfamily M transporter

member 4

TRPM5 Transient receptor potential 29850 Channel or Channel Vgic cation channel subfamily M transporter

member 5

TRPM6 Transient receptor potential 140803 Channel or Channel Vgic cation channel subfamily M transporter

member 6

TRPM7 Transient receptor potential 54822 Channel or Channel Vgic Approved Approved name Entrez Gene type / Category Ion Symbol Gene ID family channel type cation channel subfamily M transporter

member 7

TRPM8 Transient receptor potential 79054 Channel or Channel Vgic

cation channel subfamily M transporter

member 8

TRPV1 Transient receptor potential 7442 Channel or Channel Vgic

cation channel subfamily V transporter

member 1

TRPV2 Transient receptor potential 51393 Channel or Channel Vgic

cation channel subfamily V transporter

member 2

TRPV3 Transient receptor potential 162514 Channel or Channel Vgic

cation channel subfamily V transporter

member 3

TRPV4 Transient receptor potential 59341 Channel or Channel Vgic

cation channel subfamily V transporter

member 4

TRPV5 Transient receptor potential 56302 Channel or Channel Vgic

cation channel subfamily V transporter

member 5

TRPV6 Transient receptor potential 55503 Channel or Channel Vgic

cation channel subfamily V transporter

member 6

Agent Modalities

A neuromodulating agent can be a number of different modalities. A neuromodulating agent can be a nucleic acid molecule (e.g., DNA molecule or RNA molecule, e.g., mRNA, guide RNA (gRNA), or inhibitory RNA molecule (e.g., siRNA, shRNA, or miRNA), or a hybrid DNA-RNA molecule), a small molecule (e.g., a neurotransmitter, an agonist, antagonist, or an epigenetic modifier), a peptide, or a polypeptide (e.g., an antibody molecule, e.g., an antibody or antigen binding fragment thereof, or a neuropeptide). A neuromodulating agent can also be a viral vector expressing a neurome gene or a cell infected with a viral vector. Any of these modalities can be a neuromodulating agent directed to target (e.g., to agonize or to inhibit) a gene or protein in a neurotransmitter, neuropeptide, neuronal growth factor, or neurome gene (e.g., biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular) pathway described herein (e.g., a gene or protein listed in Tables 1 A-1 C, Table 7, or Table 8).

The nucleic acid molecule, small molecule, peptide, polypeptide, or antibody molecule can be modified. For example, the modification can be a chemical modification, e.g., conjugation to a marker, e.g., fluorescent marker or a radioactive marker. In other examples, the modification can include conjugation to a molecule that enhances the stability or half-life of the neuromodulating agent. The modification can also include conjugation to an antibody to target the agent to a particular cell or tissue. Additionally, the modification can be a chemical modification, packaging modification (e.g., packaging within a nanoparticle or microparticle), or targeting modification to prevent the agent from crossing the blood brain barrier.

Small Molecules

Numerous small molecule neuromodulating agents useful in the methods of the invention are described herein and additional small molecule neuromodulating agents useful as therapies for cancer can also be screened based on their ability to modulate sympathetic and parasympathetic neural pathways. Small molecules include, but are not limited to, small peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, synthetic polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic and inorganic compounds (including heterorganic and organomettallic compounds) generally having a molecular weight less than about 5,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 2,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 1 ,000 grams per mole, e.g., organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

In some embodiments, the neuromodulating agent is an agonist or antagonist listed in column 2 or column 3 of Table 2A or column 2 of Tables 2B-2L, which is directed to the corresponding

neurotransmitter pathway member listed in column 1 of Tables 2A-2L. In some embodiments, the neuromodulating agent is a neurotransmitter or neuropeptide listed in Table 1 A, 1 B, or encoded by a gene in Table 7, or a neuronal growth factor listed in Table 1 C or encoded by a gene in Table 7. Agonists and antagonists can be used to treat a disorder or condition described herein. A pharmaceutical composition comprising the agonist, antagonist, neurotransmitter, neuropeptide, or neuronal growth factor can be formulated for treatment of a cancer described herein. In some embodiments, a pharmaceutical composition that includes the agonist or antagonist is formulated for local administration, e.g., to the affected site in a subject.

Polypeptides

In embodiments, a neuromodulating agent described herein comprises a neuromodulating agent polypeptide or an analog thereof. For example, a neuromodulating agent described herein is a neuropeptide or an analog thereof.

The neuromodulating agent can be a neuropeptide listed in Table 1 A or 1 B, a neuronal growth factor listed in Table 1 C, or a protein encoded by a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular protein), wherein the primary sequence of the neuromodulating agent is provided by reference to accession number or Entrez Gene ID. The agent can be a polypeptide having the sequence referenced by accession number or Entrez Gene ID of a neuropeptide listed in Table 1 A or 1 B, a neuronal growth factor listed in Table 1 C, or a protein encoded by a neurome gene listed in Table 7, or an analog thereof, e.g., a sequence having at least 75%, 80%, 85%, 90%, 90%, 98%, 99% or 100% identity to the sequence referenced by accession number or Entrez Gene ID.

Percent identity in the context of two or more polypeptide sequences or nucleic acids, refers to two or more sequences that are the same. Two sequences are "substantially identical" if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (e.g., at least 60% identity, e.g., at least 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity, e.g., over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using a sequence comparison algorithms or by manual alignment and visual inspection. In some cases, the identity (or substantial identity) exists over a region that is at least about 50 nucleotides (or 10 amino acids) in length, or more preferably over a region that is 100 to 500 or 1 000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482c, 1 970, by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443, 1970, by the search for similarity method of Pearson and Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444, 1988, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer

Group, 575 Science Dr., Madison, Wl), or by manual alignment and visual inspection (see, e.g., Brent et al., Current Protocols in Molecular Biology, 2003).

Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389, 1977; and Altschul et al., J. Mol. Biol. 215:403, 1990, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology

Information.

The percent identity between two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci. 4:1 1 , 1 988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch, J. Mol. Biol. 48:444, 1970) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 1 6, 14, 12, 10, 8, 6, or 4 and a length weight of 1 , 2, 3, 4, 5, or 6. Methods of making a therapeutic polypeptide are routine in the art. See, in general, Smales & James (Eds.), Therapeutic Proteins: Methods and Protocols (Methods in Molecular Biologyl, Humana Press 2005; and Crommelin, Sindelar & Meibohm (Eds.), Pharmaceutical Biotechnology: Fundamentals and Applications, Springer 2013.

Some methods for producing a neuromodulating agent polypeptide involve expression in mammalian cells, although recombinant proteins can also be produced using insect cells, yeast, bacteria, or other cells under the control of appropriate promoters. Mammalian expression vectors may comprise nontranscribed elements such as an origin of replication, a suitable promoter and enhancer, and other 5' or 3' flanking nontranscribed sequences, and 5' or 3' nontranslated sequences such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and termination sequences. DNA sequences derived from the SV40 viral genome, for example, SV40 origin, early promoter, enhancer, splice, and polyadenylation sites may be used to provide the other genetic elements required for expression of a heterologous DNA sequence. Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described in Green & Sambrook, Molecular Cloning: A Laboratory Manual (Fourth Edition), Cold Spring Harbor Laboratory Press 2012.

Various mammalian cell culture systems can be employed to express and manufacture recombinant protein. Examples of mammalian expression systems include CHO cells, COS cells, HeLA and BHK cell lines. Processes of host cell culture for production of protein therapeutics are described in Zhou and Kantardjieff (Eds.), Mammalian Cell Cultures for Biologies Manufacturing (Advances in Biochemical Engineering/Biotechnology), Springer 2014.

Purification of protein therapeutics is known and is described, e.g., in Franks, Protein

Biotechnology: Isolation, Characterization, and Stabilization, Humana Press 2013; and in Cutler, Protein Purification Protocols (Methods in Molecular Biology), Humana Press 2010.

Formulation of protein therapeutics is known and is described, e.g., in Meyer (Ed.), Therapeutic Protein Drug Products: Practical Approaches to formulation in the Laboratory, Manufacturing, and the Clinic, Woodhead Publishing Series 2012.

Antibodies

The neuromodulating agent can be an antibody or antigen binding fragment thereof. For example, a neuromodulating agent described herein is an antibody that blocks or potentiates activity and/or function of a receptor, neuropeptide, neurotransmitter or transporter listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene).

The making and use of therapeutic antibodies against a target antigen (e.g., against a protein in a neurotransmitter pathway described herein (e.g., a protein product of a gene listed in Table 1 )) is known in the art. See, for example, the references cited herein above, as well as Zhiqiang An (Editor),

Therapeutic Monoclonal Antibodies: From Bench to Clinic. 1 st Edition. Wiley 2009, and also Greenfield (Ed.), Antibodies: A Laboratory Manual. (Second edition) Cold Spring Harbor Laboratory Press 2013, for methods of making recombinant antibodies, including antibody engineering, use of degenerate oligonucleotides, 5'-RACE, phage display, and mutagenesis; antibody testing and characterization; antibody pharmacokinetics and pharmacodynamics; antibody purification and storage; and screening and labeling techniques.

Synthetic mRNA

In some embodiments, the neuromodulating agent is an mRNA molecule, e.g., a synthetic mRNA molecule encoding a protein listed in Tables 1 A-1 C, or a protein encoded by a gene in Table 7 or Table 8. The mRNA molecule may increase the level (e.g., protein and/or mRNA level) and/or activity or function of a neurotransmitter, neurotransmitter receptor, neuropeptide, neuropeptide receptor, neuronal growth factor, or neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), e.g., a positive regulator of function. The mRNA molecule can encode a neuromodulating agent or a fragment thereof. For example, the mRNA molecule encodes a polypeptide having at least 50% (e.g., at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or greater) identity to the amino acid sequence of a neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. In other examples, the mRNA molecule has at least 50% (e.g., at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or greater) identity to the nucleic acid sequence of a neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene). The mRNA molecule can encode an amino acid sequence differing by no more than 30 (e.g., no more than 30, 20, 10, 5, 4, 3, 2, or 1 ) amino acids to the amino acid sequence of a neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. The mRNA molecule can have a sequence encoding a fragment of a neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. For example, the fragment comprises 10-20, 20-40, 40-60, 60-80, 80-1 00, 100-120, 120-140, 140-160, 160-180, 180-200, 200-250, 250-300, 300-400, 400-500, 500-600, or more amino acids in length. In embodiments, the fragment is a functional fragment, e.g., having at least 20%, e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater, of an activity of a full length neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. In embodiments, the mRNA molecule increases the level and/or activity or function of or encodes a neuromodulating agent (or fragment thereof).

The synthetic mRNA molecule can be modified, e.g., chemically. The mRNA molecule can be chemically synthesized or transcribed in vitro. The mRNA molecule can be disposed on a plasmid, e.g., a viral vector, bacterial vector, or eukaryotic expression vector. In some examples, the mRNA molecule can be delivered to cells by transfection, electroporation, or transduction (e.g., adenoviral or lentiviral transduction).

In some embodiments, the modified RNA encoding a neuromodulating agent of interest described herein has modified nucleosides or nucleotides. Such modifications are known and are described, e.g., in WO2012019168. Additional modifications are described, e.g., in WO2015038892; WO2015038892; WO201508951 1 ; WO2015196130; WO20151961 18 and WO2015196128A2.

In some embodiments, the modified RNA encoding a polypeptide of interest described herein has one or more terminal modifications, e.g., a 5' Cap structure and/or a poly-A tail (e.g., of between 100-200 nucleotides in length). The 5' cap structure may be selected from the group consisting of CapO, Capl, ARCA, inosine, Nl-methyl-guanosine, 2' fluoro- guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2- amino-guanosine, LNA-guanosine, and 2-azido-guanosine. In some cases, the modified RNAs also contain a 5 ' UTR comprising at least one Kozak sequence, and a 3 ' UTR. Such modifications are known and are described, e.g., in WO2012135805 and WO2013052523. Additional terminal modifications are described, e.g., in WO2014164253 and WO201601 1306. WO2012045075 and WO2014093924

Chimeric enzymes for synthesizing capped RNA molecules (e.g., modified mRNA) which may include at least one chemical modification are described in WO2014028429.

In some embodiments, a modified mRNA may be cyclized, or concatemerized, to generate a translation competent molecule to assist interactions between poly-A binding proteins and 5 '-end binding proteins. The mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1 ) chemical, 2) enzymatic, and 3) ribozyme catalyzed. The newly formed 5'-/3'- linkage may be intramolecular or intermolecular. Such modifications are described, e.g., in WO2013151736.

Methods of making and purifying modified RNAs are known and disclosed in the art. For example, modified RNAs are made using only in vitro transcription (IVT) enzymatic synthesis. Methods of making IVT polynucleotides are known in the art and are described in WO2013151 666, WO2013151668, WO2013151663, WO2013151669, WO2013151 670, WO2013151 664, WO2013151665, WO2013151 671 , WO2013151672, WO2013151667 and WO2013151736.S Methods of purification include purifying an RNA transcript comprising a polyA tail by contacting the sample with a surface linked to a plurality of thymidines or derivatives thereof and/or a plurality of uracils or derivatives thereof (polyT/U) under conditions such that the RNA transcript binds to the surface and eluting the purified RNA transcript from the surface (WO2014152031 ); using ion (e.g., anion) exchange chromatography that allows for separation of longer RNAs up to 10,000 nucleotides in length via a scalable method (WO2014144767); and subjecting a modified mRNA sample to DNAse treatment (WO2014152030).

Formulations of modified RNAs are known and are described, e.g., in WO2013090648. For example, the formulation may be, but is not limited to, nanoparticles, poly(lactic-co-glycolic acid)(PLGA) microspheres, lipidoids, lipoplex, liposome, polymers, carbohydrates (including simple sugars), cationic lipids, fibrin gel, fibrin hydrogel, fibrin glue, fibrin sealant, fibrinogen, thrombin, rapidly eliminated lipid nanoparticles (reLNPs) and combinations thereof.

Modified RNAs encoding polypeptides in the fields of human disease, antibodies, viruses, and a variety of in vivo settings are known and are disclosed in for example, Table 6 of International Publication Nos. WO2013151 666, WO2013151668, WO2013151663, WO2013151 669, WO2013151670,

WO2013151664, WO2013151665, and WO2013151736; Tables 6 and 7 of International Publication No. WO2013151672; Tables 6, 178 and 179 of International Publication No. WO2013151671 ; Tables 6, 185 and 186 of International Publication No. WO2013151667. Any of the foregoing may be synthesized as an IVT polynucleotide, chimeric polynucleotide or a circular polynucleotide, and each may comprise one or more modified nucleotides or terminal modifications.

Inhibitory RNA

In some embodiments, the neuromodulating agent is an inhibitory RNA molecule, e.g., that acts by way of the RNA interference (RNAi) pathway. An inhibitory RNA molecule can decrease the expression level (e.g., protein level or mRNA level) of a neurotransmitter, neuropeptide, receptor, neuronal growth factor, or neurome gene listed herein. For example, an inhibitory RNA molecule includes a short interfering RNA, short hairpin RNA, and/or a microRNA that targets a full length neuromodulating agent listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. A siRNA is a double-stranded RNA molecule that typically has a length of about 19-25 base pairs. A shRNA is a RNA molecule comprising a hairpin turn that decreases expression of target genes via RNAi. shRNAs can be delivered to cells in the form of plasmids, e.g., viral or bacterial vectors, e.g., by transfection, electroporation, or transduction). A microRNA is a non-coding RNA molecule that typically has a length of about 22 nucleotides. MiRNAs bind to target sites on mRNA molecules and silence the mRNA, e.g., by causing cleavage of the mRNA, destabilization of the mRNA, or inhibition of translation of the mRNA. In embodiments, the inhibitory RNA molecule decreases the level and/or activity of a negative regulator of function or a positive regulator of function. In other embodiments, the inhibitor RNA molecule decreases the level and/or activity of an inhibitor of a positive regulator of function.

An inhibitory RNA molecule can be modified, e.g., to contain modified nucleotides, e.g., 2'-fluoro, 2'-o-methyl, 2'-deoxy, unlocked nucleic acid, 2'-hydroxy, phosphorothioate, 2'-thiouridine, 4'-thiouridine, 2'-deoxyuridine. Without being bound by theory, it is believed that certain modification can increase nuclease resistance and/or serum stability, or decrease immunogenicity.

In some embodiments, the inhibitory RNA molecule decreases the level and/or activity or function of a neuromodulating agent. In embodiments, the inhibitory RNA molecule inhibits expression of a neuromodulating agent (e.g., inhibits translation to protein). In other embodiments, the inhibitor RNA molecule increases degradation of a neuromodulating agent and/or decreases the stability (i.e., half-life) of a neuromodulating agent. The inhibitory RNA molecule can be chemically synthesized or transcribed in vitro.

The making and use of inhibitory therapeutic agents based on non-coding RNA such as ribozymes, RNAse P, siRNAs, and miRNAs are also known in the art, for example, as described in Sioud, RNA Therapeutics: Function, Design, and Delivery (Methods in Molecular Biology). Humana Press 201 0.

Gene Editing

In some embodiments, the neuromodulating agent is a component of a gene editing system. For example, the neuromodulating agent introduces an alteration (e.g., insertion, deletion (e.g., knockout), translocation, inversion, single point mutation, or other mutation) in a gene related to a neurotransmitter pathway, e.g., a neuropeptide or receptor gene described in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. Exemplary gene editing systems include the zinc finger nucleases (ZFNs), Transcription Activator-Like Effector-based Nucleases (TALEN), and the clustered regulatory interspaced short palindromic repeat (CRISPR) system. ZFNs, TALENs, and CRISPR-based methods are described, e.g., in Gaj et al. Trends Biotechnol. 31 .7(2013):397-405.

CRISPR refers to a set of (or system comprising a set of) clustered regularly interspaced short palindromic repeats. A CRISPR system refers to a system derived from CRISPR and Cas (a CRISPR- associated protein) or other nuclease that can be used to silence or mutate a gene described herein. The CRISPR system is a naturally occurring system found in bacterial and archeal genomes. The CRISPR locus is made up of alternating repeat and spacer sequences. In naturally-occurring CRISPR systems, the spacers are typically sequences that are foreign to the bacterium (e.g., plasmid or phage sequences). The CRISPR system has been modified for use in gene editing (e.g., changing, silencing, and/or enhancing certain genes) in eukaryotes. See, e.g., Wiedenheft et al., Nature 482: 331 , 2012. For example, such modification of the system includes introducing into a eukaryotic cell a plasmid containing a specifically-designed CRISPR and one or more appropriate Cas proteins. The CRISPR locus is transcribed into RNA and processed by Cas proteins into small RNAs that comprise a repeat sequence flanked by a spacer. The RNAs serve as guides to direct Cas proteins to silence specific DNA/RNA sequences, depending on the spacer sequence. See, e.g., Horvath et al., Science 327: 1 67, 201 0;

Makarova et al., Biology Direct 1 :7, 2006; Pennisi, Science 341 : 833, 2013. In some examples, the CRISPR system includes the Cas9 protein, a nuclease that cuts on both strands of the DNA. See, e.g., i.d.

In some embodiments, in a CRISPR system for use described herein, e.g., in accordance with one or more methods described herein, the spacers of the CRISPR are derived from a target gene sequence, e.g., from a sequence (with reference to the accession number) of a neurotransmitter pathway gene, e.g., a neuropeptide or receptor gene listed in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided.

In some embodiments, the neuromodulating agent includes a guide RNA (gRNA) for use in a clustered regulatory interspaced short palindromic repeat (CRISPR) system for gene editing. In embodiments, the neuromodulating agent comprises a zinc finger nuclease (ZFN), or an mRNA encoding a ZFN, that targets (e.g., cleaves) a nucleic acid sequence (e.g., DNA sequence) of a gene related to a neurotransmitter pathway, e.g., a neuropeptide or receptor gene described in Table 1 . In embodiments, the neuromodulating agent comprises a TALEN, or an mRNA encoding a TALEN, that targets (e.g., cleaves) a nucleic acid sequence (e.g., DNA sequence) in a gene related to a neurotransmitter pathway, e.g., a neuropeptide or receptor gene described in Table 1 A, a ligand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, Iigand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided.

For example, the gRNA can be used in a CRISPR system to engineer an alteration in a gene (e.g., a gene related to a neurotransmitter pathway, e.g., a neuropeptide, neurotransmitter, neuronal growth factor or receptor gene described in Tables 1 A, 1 B, or 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, Iigand, receptor, signaling, synaptic, structural, or vesicular gene)). In other examples, the ZFN and/or TALEN can be used to engineer an alteration in a gene (e.g., a gene related to a neurotransmitter pathway, e.g., a neuropeptide, neurotransmitter, neuronal growth factor, or receptor gene described in Tables 1 A, 1 B, or 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, Iigand, receptor, signaling, synaptic, structural, or vesicular gene)). Exemplary alterations include insertions, deletions (e.g., knockouts), translocations, inversions, single point mutations, or other mutations. The alteration can be introduced in the gene in a cell, e.g., in vitro, ex vivo, or in vivo. In some examples, the alteration increases the level and/or activity of a neuromodulator, e.g., the alteration is a positive regulator of function. In other examples, the alteration decreases the level and/or activity of (e.g., knocks down or knocks out) a neuromodulator, e.g., the alteration is a negative regulator of function. In yet another example, the alteration corrects a defect (e.g., a mutation causing a defect), in a gene related to a neurotransmitter pathway, e.g., a neuropeptide or receptor gene described in Table 1 A, a Iigand listed in Table 1 B, a neuronal growth factor listed in Table 1 C, or a neurome gene listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, Iigand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided.

In certain embodiments, the CRISPR system is used to edit (e.g., to add or delete a base pair) a target gene, e.g., a neuromodulating agent, e.g., described herein. In other embodiments, the CRISPR system is used to introduce a premature stop codon, e.g., thereby decreasing the expression of a target gene. In yet other embodiments, the CRISPR system is used to turn off a target gene in a reversible manner, e.g., similarly to RNA interference. In embodiments, the CRISPR system is used to direct Cas to a promoter of a neuromodulator, e.g., described herein, for example, thereby blocking an RNA polymerase sterically.

In some embodiments, a CRISPR system can be generated to edit a neuromodulator (e.g., a gene related to a neurotransmitter pathway, e.g., a neuropeptide or receptor gene described in Table 1 A- 1 C), using technology described in, e.g., U.S. Publication No. 20140068797; Cong, Science 339: 81 9, 2013; Tsai, Nature Biotechnol., 32:569, 2014; and U.S. Patent Nos.: 8,871 ,445; 8,865,406; 8,795,965; 8,771 ,945; and 8,697,359.

In some embodiments, the CRISPR interference (CRISPRi) technique can be used for transcriptional repression of specific genes, e.g., a gene encoding a neuromodulating agent (e.g., a neuropeptide, neurotransmitter, neuronal growth factor, neurome gene, or receptor described herein). In CRISPRi, an engineered Cas9 protein (e.g., nuclease-null dCas9, or dCas9 fusion protein, e.g., dCas9- KRAB or dCas9-SID4X fusion) can pair with a sequence specific guide RNA (sgRNA). The Cas9-gRNA complex can block RNA polymerase, thereby interfering with transcription elongation. The complex can also block transcription initiation by interfering with transcription factor binding. The CRISPRi method is specific with minimal off-target effects and is multiplexable, e.g., can simultaneously repress more than one gene (e.g., using multiple gRNAs). Also, the CRISPRi method permits reversible gene repression.

In some embodiments, CRISPR-mediated gene activation (CRISPRa) can be used for transcriptional activation, e.g., of one or more genes described herein, e.g., a neuromodulating agent (e.g., a neuropeptide, neurotransmitter, neuronal growth factor, neurome gene, or receptor described herein). In the CRISPRa technique, dCas9 fusion proteins recruit transcriptional activators. For example, dCas9 can be used to recruit polypeptides (e.g., activation domains) such as VP64 or the p65 activation domain (p65D) and used with sgRNA (e.g., a single sgRNA or multiple sgRNAs), to activate a gene or genes, e.g., endogenous gene(s). Multiple activators can be recruited by using multiple sgRNAs - this can increase activation efficiency. A variety of activation domains and single or multiple activation domains can be used. In addition to engineering dCas9 to recruit activators, sgRNAs can also be engineered to recruit activators. For example, RNA aptamers can be incorporated into a sgRNA to recruit proteins (e.g., activation domains) such as VP64. In some examples, the synergistic activation mediator (SAM) system can be used for transcriptional activation. In SAM, MS2 aptamers are added to the sgRNA. MS2 recruits the MS2 coat protein (MCP) fused to p65AD and heat shock factor 1 (HSF1 ).

The CRISPRi and CRISPRa techniques are described in greater detail, e.g., in Dominguez et al., Nat. Rev. Mol. Cell Biol. 17:5, 2016, incorporated herein by reference. In addition, dCas9-mediated epigenetic modifications and simultaneous activation and repression using CRISPR systems, as described in Dominguez et al., can be used to modulate a thymic function modulator or thymic function factor described herein.

Viral Vectors

The neuromodulating agent can be a viral vector (e.g., a viral vector expressing a neurome gene). Viral vectors can be used to express a transgene encoding a neurotransmitter, neuropeptide, receptor, or neuronal growth factor from Tables 1 A-1 C or a neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene), all with reference to accession number or Entrez Gene ID provided. A viral vector may be administered to a cell or to a subject (e.g., a human subject or animal model) to increase expression of a neurotransmitter, neuropeptide, receptor, or neuronal growth factor from Tables 1 A-1 C or a neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene). Viral vectors can also be used to express a neurotoxin from Table 3. A viral vector expressing a neurotoxin from Table 3 can be administered to a cell or to a subject (e.g., a human subject or animal model) to decrease neurotransmission. Viral vectors can be directly administered (e.g., injected) to a or tumor to treat cancer.

Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into a mammalian cell. Viral genomes are particularly useful vectors for gene delivery because the polynucleotides contained within such genomes are typically incorporated into the nuclear genome of a mammalian cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents in order to induce gene integration. Examples of viral vectors include a retrovirus (e.g., Retroviridae family viral vector), adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses, such as picornavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvirus (e.g., Herpes Simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus, replication deficient herpes virus), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses include Norwalk virus, togavirus, flavivirus, reoviruses, papovavirus, hepadnavirus, human papilloma virus, human foamy virus, and hepatitis virus, for example. Examples of retroviruses include: avian leukosis-sarcoma, avian C-type viruses, mammalian C-type, B-type viruses, D- type viruses, oncoretroviruses, HTLV-BLV group, lentivirus, alpharetrovirus, gammaretrovirus, spumavirus (Coffin, J. M., Retroviridae: The viruses and their replication, Virology (Third Edition)

Lippincott-Raven, Philadelphia, 1996). Other examples include murine leukemia viruses, murine sarcoma viruses, mouse mammary tumor virus, bovine leukemia virus, feline leukemia virus, feline sarcoma virus, avian leukemia virus, human T-cell leukemia virus, baboon endogenous virus, Gibbon ape leukemia virus, Mason Pfizer monkey virus, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and lentiviruses. Other examples of vectors are described, for example, in US Patent No.

5,801 ,030, the teachings of which are incorporated herein by reference.

Screening for new agents

The invention also features a method of screening for an agent for the treatment of cancer. The method includes (a) providing a plurality of test agents, (b) evaluating the plurality of test agents for neuromodulating activity, and (c) selecting a test agent of the plurality as an anti-cancer if the test agent exhibits neuromodulating activity. The evaluation method can include introducing one or more test agents into a co-culture system containing at least one neuronal cell and at least one non-neuronal cell.

In certain embodiments, evaluating an agent for neuromodulating activity includes one or more of evaluating the agent for: ability to inhibit or potentiate a beta adrenergic pathway, ability to inhibit or potentiate a cholinergic pathway, ability to inhibit or potentiate a dopaminergic pathway, ability to inhibit or potentiate a serotonin pathway, ability of the agent to increase or decrease neurogenesis; ability to potentiate or inhibit the transmission of a nerve impulse; ability of the agent to increase or decrease neurome gene expression; ability of the agent to increase neurite (e.g., axon or dendrite) outgrowth ; ability to increase or decrease synapse formation or maintenance; ability to increase or decrease neuropeptide signaling; or ability to increase or decrease innervation of a tissue or tumor. The method can include correlating the neuromodulating effect of an agent with a predicted effect of the agent on a mammal, e.g., a human, e.g., by providing (e.g., to the government, a health care provider, insurance company or patient) informational, marketing or instructional material, e.g., print material or computer readable material (e.g., a label, patient record or email), related to the agent or its use, identifying the agent as a possible or predicted treatment in a mammal, e.g., a human. The method can include identifying the agent as a treatment for, or lead compound for treatment of, cancer, e.g., a condition described herein. The identification can be in the form of informational, marketing or instructional material. In one embodiment, the methods include correlating a value for neuromodulation activity with ability to treat a cancer described herein by, e.g., generating a dataset of the correlation. Evaluating the effect of the agent on neuromodulation can include administering the agent in- vivo to an experimental mammal, or in-vitro or ex-vivo to a nerve or nervous tissue of an animal and evaluating the effect of the agent on the mammal, nerve or nervous tissue. In some embodiments, the evaluation includes entering a value for the evaluation, e.g., into a database or other record. In some embodiments, the subject is an experimental animal, e.g., a wild-type or a transgenic experimental animal.

In some embodiments, the identifying step includes: (a) contacting the agent with a cell or tissue or non-human animal whose genome includes an exogenous nucleic acid that includes a regulatory region of a neuroactive protein, operably linked to a nucleotide sequence encoding a reporter polypeptide (e.g., a light based, e.g., a colorimeteric (e.g., LacZ) or flourescently detectable label, e.g., a fluorescent reporter polypeptide, e.g., GFP, EGFP, BFP, RFP); (b) evaluating the ability of a test agent to modulate the expression of the reporter polypeptide in the cell, tissue or non-human animal; and (c) selecting a test agent that modulates the expression of the reporter polypeptide as an agent that is useful in the treatment of cancer or an inflammatory or autoimmune condition described herein. In one embodiment, the cell or tissue is a nerve cell or tissue. In another embodiment, the non-human animal is a transgenic animal, e.g., a transgenic rodent, e.g., a mouse, rat or guinea pig, harboring the nucleic acid.

The test agents can be, e.g., nucleic acids (e.g., antisense RNA, ribozymes, modified mRNAs encoding an agent protein), polypeptides (antibodies or antigen-binding fragment thereof), peptide fragments, peptidomimetics, or small molecules (e.g., a small organic molecule with a molecular weight of less than 2000 daltons). In another embodiment, the test agent is a member of a combinatorial library, e.g., a peptide, antibody or organic combinatorial library, or a natural product library. In some embodiments, a plurality of test agents, e.g., library members, is tested. The test agents of the plurality, e.g., library, may share structural or functional characteristics. The test agent can also be a crude or semi-purified extract, e.g., a botanical extract such as a plant extract, or algal extract.

In one embodiment, the method includes two evaluating steps, e.g., the method includes a first step of evaluating the test agent in a first system, e.g., an in-vitro or cell-based or tissue system, and a second step of evaluating the test agent in a second system, e.g., a second cell or tissue system or in a non-human experimental animal (e.g., a rodent, a pig, a dog, a non-human primate). In other embodiments, the methods include two evaluating steps in the same type of system, e.g., the agent is re- evaluated in a non-human animal after a first evaluation in the same or a different non-human animal. The two evaluations can be separated by any length of time, e.g., days, weeks, months or years.

In some embodiments, the plurality of test agents are agents that do not cross the blood brain barrier. In some embodiments, the plurality of test agents is evaluated for ability to cross the blood brain barrier.

II. Blood Brain Barrier Permeability

In some embodiments, the neuromodulating agents for use in the present invention are agents that are not capable of crossing, or that do not cross, the blood brain barrier (BBB) of a mammalian subject. The BBB is a highly selective semipermeable membrane barrier that separates the circulating blood from the brain extracellular fluid (e.g., cerebrospinal fluid) in the central nervous system (CNS). The BBB is made up of high-density endothelial cells, which are connected by tight junctions. These cells prevent most molecular compounds in the bloodstream (e.g., large molecules and hydrophilic molecules) from entering the brain. Water, some gases (e.g., oxygen and carbon dioxide), and lipid-soluble molecules (e.g., hydrophobic molecules, such as steroid hormones) can cross the BBB by passive diffusion. Molecules that are needed for neural function, such as glucose and amino acids, are actively transported across the BBB.

A number of approaches can be used to render an agent BBB impermeable. These methods include modifications to increase an agent's size, polarity, or flexibility or reduce its lipophilicity, targeting approaches to direct an agent to another part of the body and away from the brain, and packaging approaches to deliver an agent in a form that does not freely diffuse across the BBB. These approaches can be used to render a BBB permeable neuromodulating agent impermeable, and they can also be used to improve the properties (e.g., cell-specific targeting) of a neuromodulating agent that does not cross the BBB. The methods that can be used to render an agent BBB impermeable are discussed in greater detail herein below. Formulation of BBB-permeable agents for enhanced cell targeting

One approach that can be used to render a neuromodulating agent BBB impermeable is to conjugate the agent to a targeting moiety that directs it somewhere other than the brain. The targeting moiety can be an antibody for a receptor expressed by the target cell (e.g., N-Acetylgalactosamine for liver transport; DGCR2, GBF1 , GPR44 or SerpinBI 0 for pancreas transport; Secretoglobin, family 1 A, member 1 for lung transport). The targeting moiety can also be a ligand of any receptor or other molecular identifier expressed on the target cell in the periphery. These targeting moieties can direct the neuromodulating agent of interest to its corresponding target cell, and can also prevent BBB crossing by directing the agent away from the BBB and increasing the size of the neuromodulating agent via conjugation of the targeting moiety.

Neuromodulating agents can also be rendered BBB impermeable through formulation in a particulate delivery system (e.g., a nanoparticle, liposome, or microparticle), such that the agent is not freely diffusible in blood and cannot cross the BBB. The particulate formulation used can be chosen based on the desired localization of the neuromodulating agent (e.g., a tumor), as particles of different sizes accumulate in different locations. For example, nanoparticles with a diameter of 45 nm or less enter the lymph node, while 100 nm nanoparticles exhibit poor lymph node trafficking. Some examples of the link between particle size and localization in vivo are described in Reddy et al., J Controlled Release 1 12:26 2006, and Reddy et al., Nature Biotechnology 25:1 159 2007.

Neuromodulating agents can be tested after the addition of a targeting moiety or after formulation in a particulate delivery system to determine whether or not they cross the BBB. Models for assessing BBB permeability include in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi- fluidic models, isolated brain microvessels), in vivo models, and computational models as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:15 2005; and Wang et al., Int J Pharm 288:349 2005. A neuromodulating agent that exhibits BBB impermeability can be used in the methods described herein. Modification of existing compounds to render them BBB impermeable There are multiple parameters that have been empirically derived in the field of medicinal chemistry to predict whether a compound will cross the BBB. The most common numeric value for describing permeability across the BBB is the logBB, defined as the logarithmic ratio of the concentration of a compound in the brain and in the blood. Empirical rules of thumb have been developed to predict BBB permeability, including rules regarding molecular size, polar surface area, sum of oxygen and nitrogen atoms, lipophilicity (e.g., partition coefficient between apolar solvent and water), "lipoaffinity", molecular flexibility, and number of rotable bonds (summarized in Muehlbacher et al., J Comput Aided Mol Des. 25: 1095 201 1 ; and Geldenhuys et al., Ther Deliv. 6: 961 201 5). Some preferred limits on various parameters for BBB permeability are listed in Table 1 of Ghose et al., ACS Chem Neurosci. 3: 50 2012, which is incorporated herein by reference. Based on the parameters shown in the table, one of skill in the art could modify an existing neuromodulating agent to render it BBB impermeable.

One method of modifying a neuromodulating agent to prevent BBB crossing is to add a molecular adduct that does not affect the target binding specificity, kinetics, or theromodynamics of the agent.

Molecular adducts that can be used to render an agent BBB impermeable include polyethylene glycol (PEG), a carbohydrate monomer or polymer, a dendrimer, a polypeptide, a charged ion, a hydrophilic group, deuterium, and fluorine. Neuromodulating agents can be tested after the addition of one or more molecular adducts or after any other properties are altered to determine whether or not they cross the BBB. Models for assessing BBB permeability include in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi-fluidic models, isolated brain microvessels), in vivo models, and computational models as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:1 5 2005; and Wang et al., Int J Pharm 288:349 2005. A neuromodulating agent that exhibits BBB impermeability can be used in the methods described herein.

Screening for or development of BBB impermeable agents

Another option for developing BBB impermeable agents is to find or develop new agents that do not cross the BBB. One method for finding new BBB impermeable agents is to screen for compounds that are BBB impermeable. Compound screening can be performed using in vitro models (e.g., monolayer models, co-culture models, dynamic models, multi-fluidic models, isolated brain microvessels), in vivo models, and computational models, as described in He et al., Stroke 45:2514 2014; Bickel, NeuroRx 2:15 2005; Wang et al., Int J Pharm 288:349 2005, and Czupalla et al., Methods Mol Biol

1 135:415 2014. For example, the ability of a molecule to cross the blood brain barrier can be determined in vitro using a transwell BBB assay in which microvascular endothelial cells and pericytes are co-cultured separated by a thin macroporous membrane, see e.g., Naik et al., J Pharm Sci 101 :1337 2012 and Hanada et al., Int J Mol Sci 15:1812 2014; or in vivo by tracking the brain uptake of the target molecule by histology or radio-detection. Compounds would be deemed appropriate for use as neuromodulating agents in the methods described herein if they do not display BBB permeability in the aforementioned models.

III. Cancer

The methods described herein can be used to treat cancer in a subject by administering to the subject an effective amount of a neuromodulating agent, e.g., a neuromodulating agent described herein The method may include administering locally (e.g., intratumorally) to the subject a neuromodulating agent described herein in a dose (e.g., effective amount) and for a time sufficient to treat the cancer.

The neuromodulating agent may inhibit proliferation or disrupt the function of non-neural cells associated with the cancer, e.g., the method includes administering to the subject an effective amount of a neuromodulating agent for a time sufficient to inhibit proliferation or disrupt the function of non-neural cells associated with the cancer. Non-neural cells associated with the cancer include malignant cancer cells, malignant cancer cells in necrotic and hypoxic areas, adipocytes, pericytes, endothelial cells, cancer associated fibroblasts, fibroblasts, mesenchymal stem cells, red blood cells, or extracellular matrix. The proliferation of non-neural cells associated with the cancer may be decreased in the subject at least 1 %, 2%, 5%, 1 0%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The proliferation of non-neural cells associated with the cancer can be decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, or between 20-70%.

The neuromodulating agent can be administered in an amount sufficient to treat cancer. For example, the stroma associated with the tumor, e.g., fibroblasts, is disrupted such that an essential function, e.g., the production of matrix metalloproteases, is altered to inhibit tumor survival or promote tumor control.

The neuromodulating agent can treat cancer by increasing cancer cell death in a subject (e.g., a human subject or animal model) or in a cancer cell culture (e.g., a culture generated from a patient tumor sample, a cancer cell line, or a repository of patient samples). A neuromodulating agent can increase cancer cell death by at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more compared to before administration to a subject or cancer cell culture. A

neuromodulating agent can increase cancer cell death in a subject or cancer cell culture between 5-20%, between 5-50%, between 1 0-50%, between 20-80%, between 20-70%.

The neuromodulating agent can also act to inhibit cancer cell growth, proliferation, metastasis, or invasion, e.g., the method includes administering to the subject (e.g., a human subject or animal model) or a cancer cell culture (e.g., a culture generated from a patient tumor sample, a cancer cell line, or a repository of patient samples) a neuromodulating agent in an amount (e.g., an effective amount) and for a time sufficient to inhibit cancer cell growth, proliferation, metastasis, or invasion. Cancer cell growth, proliferation, metastasis, or invasion can be decreased in the subject or cancer cell culture at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration Cancer cell growth, proliferation, metastasis, or invasion can be decreased in the subject or cancer cell culture between 5-20%, between 5-50%, between 1 0-50%, between 20-80%, between 20-70%.

The neuromodulating agent can inhibit cancer cell invasion or metastasis along a nerve, e.g., the method includes administering to the subject (e.g., a human subject or animal model) a neuromodulating agent in an amount (e.g., an effective amount) and for a time sufficient to inhibit cancer cell invasion or metastasis along a nerve. For example, the neuromodulating agent is an antibody against a ligand selected from: Galanin; Semaphorin-4F; Caveolin-1 ; a chemokine such as CCL2, CCR2, CXCL12, and CXCR4; GDNF; GFRal ; NGF; neurotrophin-3 or -4; substance P; Neuropeptide Y; Peptide YY;

Vasoactive intestinal peptide (VIP); or NCAM1 . In other examples, the neuromodulating agent can be a receptor antagonist against the receptor for a ligand selected from: Galanin; Semaphorin-4F; Caveolin-1 ; a chemokine such as CCL2, CCR2, CXCL12, and CXCR4; GDNF; GFRal ; NGF; neurotrophin-3 or -4; substance P; Neuropeptide Y; Peptide YY; Vasoactive intestinal peptide (VIP); or NCAM1 . The neuromodulating can decrease cancer cell invasion or metastasis along a nerve in the subject at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The neuromodulating agent can decrease cancer cell invasion or metastasis along a nerve in the subject between 5-20%, between 5-50%, between 10-50%, between 20- 80%, between 20-70%.

The neuromodulating agent can also reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. For example, the method includes administering to the subject (e.g., a human subject or animal model) a neuromodulating agent in an amount (e.g., an effective amount) and for a time sufficient to reduce the number of nerve fibers in the affected tissue or reduce the activity of peripheral nerve fibers in the affected tissue. The affected tissue can be a tumor, a tumor micro-environment, or the bone marrow niche. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, compared to before the administration. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be decreased in the subject between 5-20%, between 5-50%, between 1 0-50%, between 20-80%, or between 20-70%.

The neuromodulating agent can also increase the number of nerve fibers in the affected tissue or increase the activity of peripheral nerve fibers in the affected tissue. For example, the method includes administering to the subject (e.g., a human subject or animal model) a neuromodulating agent in an amount (e.g., an effective amount) and for a time sufficient to increase the number of nerve fibers in the affected tissue or increase the activity of peripheral nerve fibers in the affected tissue. The affected tissue can be a tumor, a tumor micro-environment, or the bone marrow niche. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be increased in the subject at least 1 %, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80% or more, compared to before the administration. The number of nerve fibers in the affected tissue or the activity of peripheral nerve fibers in the affected tissue can be increased in the subject between 5-20%, between 5- 50%, between 10-50%, between 20-80%, or between 20-70%.

The nerve fibers that are modulated can be part of the peripheral nervous system, e.g., a somatic nerve, an autonomic nerve, a sensory nerve, a cranial nerve, an optic nerve, an olfactory nerve, a sympathetic nerve, a parasympathetic nerve, a chemoreceptor, a photoreceptor, a mechanoreceptor, a thermoreceptor, a nociceptor, an efferent nerve fiber, or an afferent nerve fiber.

The methods described herein can also be used to treat a subject who has cancer by administering to a subject having a cancer listed in column 2 of Table 10 a neuromodulating agent that modulates the activity and/or function of a correspondingly listed gene in column 1 of Table 10, in an amount (e.g., an effective amount) and for a time sufficient to treat the subject. The neuromodulating agent can be a neuropeptide having the sequence referenced by accession number of a neuropeptide listed in column 3 of Table 10 for the corresponding gene, or an analog or fragment thereof, e.g., a sequence having at least 75%, 80%, 85%, 90%, 90%, 98%, or 99% identity to the sequence referenced by accession number.

The methods described herein can be used to treat a subject with neuro-dependent cancer (e.g., cancer that expresses one or more neurome genes listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene)). The

neuromodulating agent can be a neurome gene expression modulator that decreases gene expression (e.g., an inhibitory RNA) in a subject with a neuro-dependent cancer that overexpresses one or more neurome genes. The neuromodulating agent can be a neurome gene expression modulator that increases gene expression (e.g., an mRNA or a viral vector encoding a neurome gene) in a subject with a neuro-dependent cancer that under-expresses one or more neurome genes. The neuromodulating agent can be an agent that increases neurotransmission or neuropeptide signaling (e.g., a neurotransmitter or neuropeptide receptor agonist) in a subject with a neuro-dependent cancer that under-expresses one or more genes needed for neurotransmission or neuropeptide signaling. The neuromodulating agent can be an agent that decreases neurotransmission or neuropeptide signaling (e.g., a neurotransmitter or neuropeptide receptor antagonist, or a neurotoxin) in a subject with a neuro-dependent cancer that overexpresses one or more genes needed for neurotransmission or neuropeptide signaling. If the subject has a neuro-dependent cancer that overexpresses a neuronal growth factor gene, the neuromodulating agent can be an agent that reduces neuronal growth factor signaling (e.g., a blocking antibody or growth factor receptor antagonist).

In the methods described herein relating to cancer, the cancer or neoplasm may be any solid or liquid cancer and includes benign or malignant tumors, and hyperplasias, including gastrointestinal cancer (such as non-metastatic or metastatic colorectal cancer, pancreatic cancer, gastric cancer, esophageal cancer, hepatocellular cancer, cholangiocellular cancer, oral cancer, lip cancer); urogenital cancer (such as hormone sensitive or hormone refractory prostate cancer, renal cell cancer, bladder cancer, penile cancer); gynecological cancer (such as ovarian cancer, cervical cancer, endometrial cancer); lung cancer (such as small-cell lung cancer and non-small-cell lung cancer); head and neck cancer (e.g., head and neck squamous cell cancer); CNS cancer including malignant glioma, astrocytomas, retinoblastomas and brain metastases; malignant mesothelioma; non-metastatic or metastatic breast cancer (e.g., hormone refractory metastatic breast cancer); skin cancer (such as malignant melanoma, basal and squamous cell skin cancers, Merkel Cell Carcinoma, lymphoma of the skin, Kaposi Sarcoma); thyroid cancer; bone and soft tissue sarcoma; and hematologic neoplasias (such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, Hodgkin's lymphoma).

Additional examples of cancers that can be treated according to the methods described herein include breast cancer, lung cancer, stomach cancer, colon cancer, liver cancer, renal cancer, colorectal cancer, prostate cancer, pancreatic cancer, cervical cancer, anal cancer, vulvar cancer, penile cancer, vaginal cancer, testicular cancer, pelvic cancer, thyroid cancer, uterine cancer, rectal cancer, brain cancer, head and neck cancer, esophageal cancer, bronchus cancer, gallbladder cancer, ovarian cancer, bladder cancer, oral cancer, oropharyngeal cancer, larynx cancer, biliary tract cancer, skin cancer, a cancer of the central nervous system, a cancer of the respiratory system, and a cancer of the urinary system. Examples of breast cancers include, but are not limited to, triple-negative breast cancer, triple- positive breast cancer, HER2-negative breast cancer, HER2-positive breast cancer, estrogen receptor- positive breast cancer, estrogen receptor-negative breast cancer, progesterone receptor-positive breast cancer, progesterone receptor-negative breast cancer, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, invasive lobular carcinoma, inflammatory breast cancer, Paget disease of the nipple, and phyllodes tumor.

Other examples of cancers that can be treated according to the methods described herein include leukemia (e.g., B-cell leukemia, T-cell leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic (lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), and erythroleukemia), sarcoma (e.g., angiosarcoma, chondrosarcoma, Ewing's sarcoma, fibrosarcoma, gastrointestinal stromal tumor, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor, malignant fibrous cytoma, osteosarcoma, pleomorphic sarcoma, rhabdomyosarcoma, synovial sarcoma, vascular sarcoma, Kaposi's sarcoma, dermatofibrosarcoma, epithelioid sarcoma, leyomyosarcoma, and neurofibrosarcoma), carcinoma (e.g., basal cell carcinoma, large cell carcinoma, small cell carcinoma, non-small cell lung carcinoma, renal carcinoma, hepatocarcinoma, gastric carcinoma, choriocarcinoma, adenocarcinoma, hepatocellular carcinoma, giant (or oat) cell carcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastmic carcinoma, adrenocortical carcinoma, cholangiocarcinoma, Merkel cell carcinoma, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma), blastoma (e.g., hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma,

pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt lymphoma), myeloma (e.g., multiple myeloma, plasmacytoma, localized myeloma, and extramedullar myeloma), melanoma (e.g., superficial spreading melanoma, nodular melanoma, lentigno maligna melanoma, acral lentiginous melanoma, and amelanotic melanoma), neuroma (e.g., ganglioneuroma, Pacinian neuroma, and acoustic neuroma), glioma (e.g., astrocytoma, oligoastrocytoma, ependymoma, brainstem glioma, optic nerve glioma, and

oligoastrocytoma), pheochromocytoma, meningioma, malignant mesothelioma, and virally induced cancer.

In some embodiments, the cancer is a paraneoplastic cancer (e.g., a cancer that causes a paraneoplastic syndrome). Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm, and are mediated by humoral factors such as hormones, cytokines, or auto-antibodies produced by the tumor. Symptoms of paraneoplastic syndrome may be endocrine, neuromuscular, or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or neurological. Paraneoplastic syndromes commonly present with lung, breast, and ovarian cancer and cancer of the lymphatic system (e.g., lymphoma). Paraneoplastic neurological disorders are disorders that affect the central or peripheral nervous system, and can include symptoms such as ataxia (difficulty with walking and balance), dizziness, nystagmus (rapid uncontrolled eye movements), difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision problems, sleep disturbances, dementia, seizures, or sensory loss in the limbs. Breast, ovarian, and lung cancers are most commonly associated with paraneoplastic neurological disorders. Other common types of paraneoplastic syndromes include paraneoplastic cerebellar degeneration, paraneoplastic pemphigus, paraneoplastic autonomic neuropathy, paraneoplastic encephalomyelitis, and cancer-associated autoimmune retinopathy. Endocrine paraneoplastic syndromes include Cushing syndrome (caused by ectopic ACTH), which is most commonly caused by small cell lung cancer, pancreatic carcinoma, neural tumors, or thymoma; SIADH (caused by antidiuretic hormone), which is most commonly caused by small cell lung cancer and CNS malignancies; hypercalcemia (caused by PTHrp, TGFa, TNF, or IL-1 ), which is most commonly caused by lung cancer, breast carcinoma, renal and bladder carcinoma, multiple myeloma, adult T cell leukemia/lymphoma, ovarian carcinoma, and squamous cell carcinoma (e.g., lung, head, neck, or esophagus carcinoma); hyperglycemia (caused by insulin insulin-like substance, or "big" IGF-II), which is most commonly caused by fibrosarcoma, mesenchymal sarcomas, insulinoma, and

hepatocellular carcinoma; carcinoid syndrome (caused by serotonin or bradykinin), which is most commonly caused by bronchial adenoma, pancreatic carcinoma, and gastric carcinoma; and

hyperaldosteronism (caused by aldosterone), which is most commonly caused by adrenal

adenoma/Conn's syndrome, non-Hodgkin's lymphoma, ovarian carcinoma, and pulmonary cancer.

Neurological paraneoplastic syndromes include Lambert-Eaton myasthenic syndrome (LEMS), which is most commonly caused by small cell lung cancer; paraneoplastic cerebellar degeneration, which is most commonly caused by lung cancer, ovarian cancer, breast carcinoma, and Hodgkin's lymphoma; encephalomyelitis; limbic encephalitis, which is most commonly caused by small cell lung carcinoma; myasthenia gravis, which is most commonly caused by thymoma; brainstem encephalitis; opsoclonus myoclonus ataxia (caused by autoimmune reaction against Nova-1 ), which is most commonly caused by breast carcinoma, ovarian carcinoma, small cell lung carcinoma, and neuroblastoma; anti-NMDA receptor encephalitis (caused by autoimmune reaction against NMDAR subunits), which is most commonly caused by teratoma; and polymyositis, which is most commonly caused by lung cancer, bladder cancer, and non- Hodgkin's lymphoma. Mucotaneous paraneoplastic syndromes include acanthosis nigricans, which is most commonly caused by gastric carcinoma, lung carcinoma, and uterine carcinoma; dermatomyositis, which is most commonly caused by bronchogenic carcinoma, breast carcinoma, ovarian cancer, pancreatic cancer, stomach cancer, colorectal cancer, and Non-Hodgkin's lymphoma; Leser-Trelat sign; necrolytic migratory erythema, which is most commonly caused by glucoganoma; Sweet's syndrome; florid cutaneous papillomatosis; pyoderma gangrenosum ; and acquired generalized hypertrichosis.

Hematological syndromes include granulocytosis (caused by G-CSF); polycythemia (caused by erythropoietin), which is commonly caused by renal carcinoma, cerebellar hemangioma, and

heptatocellular carcinoma; Trousseau sign (caused by mucins), which is commonly caused by pancreatic carcinoma and bronchogenic carcinoma; nonbacterial thrombotic endocarditis, which is caused by advanced cancers; and anemia, which is most commonly caused by thymic neoplasms. Other paraneoplastic syndromes include membranous glomerular nephritis; neoplastic fever; Staffer syndrome, which is caused by renal cell carcinoma; and tumor-induced osteomalacia (caused by FGF23), which is caused by hemangiopericytoma and phosphaturic mesenchymal tumor.

In some embodiments, a subject is identified as having cancer after presenting with symptoms of a paraneoplastic syndrome. A common symptom of paraneoplastic syndrome is fever. Auto-antibodies directed against nervous system proteins are also frequently observed in patients with paraneoplastic syndromes, including anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-CV2, anti-Ma2, anti-recoverin, anti- transducin, anti-carbonic anhydrase II, anti-arrestin, anti-GCAP1 , anti-GCAP2, anti-HSP27, anti-Rab6A, and anti-PNR. Other symptoms that can be used to identify a patient with paraneoplastic cancer include ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision loss, sleep disturbances, dementia, seizures, dysgeusia, cachexia, anemia, itching, or sensory loss in the limbs. In some embodiments, a patient presents with symptoms of paraneoplastic syndrome and is then identified as having cancer based on imaging tests (e.g., CT, MRI, or PET scans).

The cancer may be highly innervated, metastatic, non-metastatic cancer, or benign (e.g., a benign tumor). The cancer may be a primary tumor or a metastasized tumor. The cancer may be neuro- dependent (e.g., a cancer cell or tumor that expresses one or more neurome genes listed in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene)). These genes include neurotransmitters, neurotransmitter receptors, neuropeptides, neuropeptide receptors, neurotransmitter transporters, neurotransmitter biogenesis or biosynthetic genes, ion channels, ion pumps, vesicular proteins, synaptic junction proteins, axonal guidance proteins, neurotrophic factors, and signaling molecules found downstream of neuronal cell surface receptors (see Table 7 for complete list). In some embodiments, the neurological gene signature (e.g., neurome gene expression profile) is unrelated to tumor type of origin. The one or more neurome genes expressed by the cancer cell or tumor can be used to determine patient treatment (e.g., the neuromodulating agent can be chosen based on the neurome gene(s) expressed by the cancer cell or tumor).

The neurome gene expression profile of a cancer cell or tumor can be determined using gene profiling. Profiling results can also be used to categorize (e.g., identify) a tumor as belonging to a neurological taxon (e.g., a neurotaxonomic group). In some embodiments, the neoplasm is placed into a group (e.g., neurotaxonomic group) based on profiling results. Placement within a neurotaxonomic group can be used to determine patient treatment (e.g., to determine which neuromodulating agent to administer). In some embodiments, the neuro-dependent tumor can be placed into one of four groups based on neurome gene expression: (family 1 ) HTR1 D, ADRA2A, CHRNA7; (family 2) ADRA2C, CHRM3; (family 3) GRM8, DRD2, CHRNB2, CHRM4; (family 4) ADRAB2, ADRA1 B. In some embodiments, the neuro-dependent tumor overexpresses one or more neurome genes. For example, the cancer cell or tumor can be a cancer listed in Table 12 that overexpresses a corresponding gene in Table 12. In some embodiments, the neuro-dependent tumor under-expresses one or more neurome genes. For example, the cancer cell or tumor can be a cancer listed in Table 13 that under-expresses a corresponding gene in Table 13. In some embodiments, the neuro-dependent tumor co-expresses one or more genes encoding a neuropeptide or neurotransmitter, or a gene necessary for the biosynthesis or recycling of a neuropeptide or neurotransmitter, and genes encoding the cognate neurotransmitter or neuropeptide receptor. For example, the cancer cell or tumor can be a cancer listed in Tables 14A-14C that expresses the corresponding biosynthetic enzyme and cognate receptor shown in Tables 14A-14C. In some embodiments, the neuro-dependent tumor expresses one or more neurotrophic factors. Neuro- dependent tumors can be identified using quantitative RT-PCR, RNA sequencing, immunohistochemistry, or western blot analysis of tumor samples.

The methods described herein can include profiling a tumor sample to determine whether it expresses one or more neurome genes (e.g., a neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene)). Profiling can be performed using RNA sequencing, microarray analysis, or serial analysis of gene expression (SAGE). Other techniques that can be used to assess gene expression include quantitative RT-PCR. Profiling results can be confirmed using methods such as immunohistochemistry, western blot analysis, or southern blot analysis. Profiling results can be used to determine which neuromodulating agent should be administered to treat the patient. In some embodiments, the methods described herein include selecting a neuromodulating agent based on the neurome gene expression profile of the tumor. For example, if a tumor expresses a neurotransmitter or neurotransmitter receptor, the neuromodulating agent can be a neurotransmission modulator or a neurome gene expression modulator. If a tumor expresses a neuropeptide or neuropeptide receptor, the neuromodulating agent can be a neuropeptide signaling modulator or a neurome gene expression modulator. If a tumor expresses a neuronal growth factor, the neuromodulating agent can be a neuronal growth factor modulator or a neurome gene expression modulator. Neuromodulating agents that decrease expression or activity can be used if the neurome gene is overexpressed, and neuromodulating agents that increase expression or activity can be used if the neurome gene is under-expressed.

Over- and under-expression can be determined by comparing expression of a neurome gene to a housekeeping gene. If the neurome gene is expressed at a higher level than the housekeeping gene (e.g., neurome gene expression is at least 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold higher than

housekeeping gene expression), the neurome gene is overexpressed. In some embodiments, the overexpressed neurome gene is a gene in Table 12 that is expressed in a corresponding cancer in Table 12. If the neurome gene is expressed at a lower level than the housekeeping gene (e.g., neurome gene expression is at least 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold lower than housekeeping gene expression), the neurome gene is under-expressed. In some embodiments, the under-expressed neurome gene is a gene in Table 13 that is under-expressed in a corresponding cancer in Table 13.

Subjects who can be treated with the methods disclosed herein include subjects who have had one or more tumors resected, received chemotherapy or other pharmacological treatment for the cancer, received radiation therapy, and/or received other therapy for the cancer. Subjects who have not previously been treated for cancer can also be treated with the methods disclosed herein.

IV. Combination therapies for cancer

Combination Therapies for Cancer

A neuromodulating agent described herein can be administered in combination with a second therapeutic agent for treatment of cancer. In some embodiments, the neuromodulating agent is selected based on the neurome gene expression profile of the cancer. In some embodiments, the second therapeutic agent is selected based on tumor type, tumor tissue of origin, tumor stage, or mutations in non-neurome genes expressed by the tumor.

Checkpoint Inhibitors

One type of agent that can be administered in combination with a neuromodulating agent described herein is a checkpoint inhibitor. Checkpoint inhibitors can be broken down into at least 4 major categories: i) agents such as antibodies that block an inhibitory pathway directly on T cells or natural killer (NK) cells (e.g., PD-1 targeting antibodies such as nivolumab and pembrolizumab, antibodies targeting TIM-3, and antibodies targeting LAG-3, 2B4, CD160, A2aR, BTLA, CGEN-15049, or KIR), ii) agents such as antibodies that activate stimulatory pathways directly on T cells or NK cells (e.g., antibodies targeting OX40, GITR, or 4-1 BB), iii) agents such as antibodies that block a suppressive pathway on immune cells or rely on antibody-dependent cellular cytotoxicity to deplete suppressive populations of immune cells (e.g., CTLA-4 targeting antibodies such as ipilimumab, antibodies targeting VISTA, and antibodies targeting PD-L2, Gr1 , or Ly6G), and iv) agents such as antibodies that block a suppressive pathway directly on cancer cells or that rely on antibody-dependent cellular cytotoxicity to enhance cytotoxicity to cancer cells (e.g., rituximab, antibodies targeting PD-L1 , and antibodies targeting B7-H3, B7-H4, Gal-9, or MUC1 ). Such agents described herein can be designed and produced, e.g., by conventional methods known in the art (e.g., Templeton, Gene and Cell Therapy, 2015; Green and Sambrook, Molecular Cloning, 2012).

Chemotherapy

A second type of therapeutic agent that can be administered in combination with a

neuromodulating agent described herein is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids,

epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxel. Non-limiting examples of

chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine,

triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin ; duocarmycin (including the synthetic analogues, KW-2189 and CB1 -TM1 ); eleutherobin ; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:1 83 1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone;

aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene;

edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone;

etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine;; razoxane; rhizoxin; sizofuran;

spirogermanium ; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;

mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., , paclitaxel; chloranbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;

platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum ; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-1 1 ); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al.,Proc ASCO 18:233a, 1999, and Douillard et al., Lancet 355:1041 , 2000.

Biologic Cancer Agents

Another type of therapeutic agent that can be administered in combination with a

neuromodulating agent described herein is a therapeutic agent that is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In other embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab. In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include Rituximab; Daclizumab; Basiliximab; Palivizumab; Infliximab; Trastuzumab; Gemtuzumab ozogamicin; Alemtuzumab; Ibritumomab tiuxetan; Adalimumab; Omalizumab; Tositumomab-l-131 ; Efalizumab;

Cetuximab; Bevacizumab; Natalizumab; Tocilizumab; Panitumumab; Ranibizumab; Eculizumab;

Certolizumab pegol; Golimumab; Canakinumab; Ustekinumab; Ofatumumab; Denosumab; Motavizumab; Raxibacumab; Belimumab; Ipilimumab; Brentuximab Vedotin; Pertuzumab; Ado-trastuzumab emtansine; and Obinutuzumab. Also included are antibody-drug conjugates. Examples of biologic cancer agents that can be used in combination with neuromodulating agents described herein are shown in Table 9 below. TABLE 9: APPROVED CANCER ANTIBODIES

Antibody Company Antigen Indication

Nivolumab Bristol-Myers PD-1 Metastatic squamous non-small cell lung

Squibb carcinoma

Obinutuzumab Genentech CD20 Chronic lymphocytic leukemia

Ofatumumab Glaxo Grp CD20 Chronic lymphocytic leukemia

Olaratumab Eli Lilly PDGFRA Soft tissue sarcoma

Panitumumab Amgen EGFR Metastatic colorectal cancer

Pembrolizumab Merck PD-1 Metastatic melanoma

Pertuzumab Genentech HER2 Metastatic breast cancer

Ramucirumab Eli Lilly VEGFR2 Gastric cancer

Rituximab Genentech CD20 B-cell non-Hodgkin's lymphoma

Trastuzumab Genentech HER2 Metastatic breast cancer

Non-Drug Therapies

Another type of agent that can be administered in combination with a neuromodulating agent is a therapeutic agent that is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and/or surgical excision of tumor tissue.

In any of the combination therapy approaches described herein, the first and second therapeutic agent (e.g., a neuromodulating agent described herein and the additional therapeutic agent) are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 1 1 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 1 9 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after the second therapeutic agent. V. Methods of Treatment

Administration

An effective amount of a neuromodulating agent described herein for treatment of cancer can be administered to a subject by standard methods. For example, the agent can be administered by any of a number of different routes including, e.g., intravenous, intradermal, subcutaneous, percutaneous injection, oral, transdermal (topical), or transmucosal. The neuromodulating agent can be administered orally or administered by injection, e.g., intramuscularly, or intravenously. The most suitable route for administration in any given case will depend on the particular agent administered, the patient, the particular disease or condition being treated, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient's age, body weight, sex, severity of the diseases being treated, the patient's diet, and the patient's excretion rate. The agent can be encapsulated or injected, e.g., in a viscous form, for delivery to a chosen site, e.g., a tumor. The agent can be provided in a matrix capable of delivering the agent to the chosen site. Matrices can provide slow release of the agent and provide proper presentation and appropriate environment for cellular infiltration. Matrices can be formed of materials presently in use for other implanted medical applications. The choice of matrix material is based on any one or more of: biocompatibility, biodegradability, mechanical properties, and cosmetic appearance and interface properties. One example is a collagen matrix.

The agent (e.g., peptide, neurotransmitter, small molecule, nucleic acid, protein such as an antibody,) can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically include the agent and a pharmaceutically acceptable carrier. As used herein the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances are known. Except insofar as any conventional media or agent is incompatible with the active compound, such media can be used in the compositions of the invention. Supplementary active compounds can also be incorporated into the compositions.

A pharmaceutical composition can be formulated to be compatible with its intended route of administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;

chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a neuromodulating agent described herein) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and

microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.

Nucleic acid molecule agents described herein can be administered directly (e.g., therapeutic mRNAs) or inserted into vectors used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen et al., PNAS 91 :3054 1994). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Methods of formulating pharmaceutical agents are known in the art, e.g., Niazi, Handbook of Pharmaceutical Manufacturing Formulations (Second Edition), CRC Press 2009, describes formulation development for liquid, sterile, compressed, semi-compressed and OTC forms. Transdermal and mucosal delivery, lymphatic system delivery, nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologies delivery are described in Wang et al., Drug

Delivery: Principles and Applications (Second Edition), Wiley 2016; formulation and delivery of peptide and protein agent is described, e.g., in Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems (Third Edition), CRC Press 2015.

The neuromodulating agents described herein may be administered in a unit dose form. For example, the methods described herein include administration of a unit dose form of a beta-adrenergic inhibitory agent. The unit dose can be less than or more than a unit dose of the beta blocker that is FDA approved for high blood pressure, a cardiac condition, angina, essential tremor, hypertrophic subaortic stenosis, migraine prophylaxis, myocardial infarction prophylaxis, pheochromocytoma, tachyarrhythmias, or thyrotoxicosis. The beta-adrenergic blocking agent can be selected from: acebutolol, atenolol, bisoprolol, metoprolol, nadolol, and propranolol. The agent can be formulated for parenteral administration, enteral administration (e.g., oral), or local administration (e.g., epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional or intra-tumoral administration).

The unit dose form can be a unit dose of a cholinergic inhibitory agent. The unit dose can be less than or more than a unit dose of the cholinergic blocker that is FDA approved for Alzheimer's Disease, Cardiac and Respiratory Disorders, Atony and Neurogenic Bladder, motion sickness, Myasthenia gravis, Peptic ulcer, IBD, Glaucoma, Parkinson's Disease, reflex neurogenic bladder (spinal cord injury), or Incontinence-overactive bladder. The cholinergic blocking agent can be selected from: tacrine, galantamine, rivastigmine, donepezil. The unit dose can be configured for local administration, e.g., epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional or intra-tumoral administration.

The unit dose form can be a unit dose of a dopaminergic inhibitory agent. The unit dose can be less than or more than a unit dose of the dopamine blocker that is FDA approved for schizophrenia, bipolar disorder, or nausea and vomiting. The dopamine blocking agent can be selected from:

acepromazine, amisulpride, amoxapine, asenapine, azaperone, benperidol, Bromopride, butaclamol, chlorpromazine, chlorprothixene, clopenthixol, Domperidone, droperidol, eticlopride, flupenthixol, fluphenazine, fluspirilene, haloperidol, hydroxyzine, iodobenzamide, loxapine, mesoridazine, levomepromazine, metoclopramide, nafadotride, nemonapride, olanzapine, paliperidone, penfluridol, perazine, perphenazine, pimozide, prochlorperazine, promazine, quetiapine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine, stepholidine, sulpiride, sultopride, tetrahydropalmatine,

thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, and ziprasidone. The unit dose can be configured for local administration, e.g., epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional or intra-tumoral administration.

The unit dose can be a unit dose of a serotonin inhibitory agent. The unit dose can be less than or more than a unit dose of the serotonin blocker that is FDA approved for treatment of a mood disorder, e.g., major depressive disorder (MDD), anxiety disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), or for the relief of menopausal symptoms. The serotonin blocking agent can be selected from: Venlafaxine, Desvenlafaxine, Duloxetine, Milnacipran Levomilnacipran, Sibutramine, and Atomoxetine. The unit dose can be configured for local administration, e.g., epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional or intra-tumoral administration.

Local administration

The neuromodulating agents described herein can be administered locally, e.g., to the site of cancer in the subject. Examples of local administration include epicutaneous, inhalational, intra-articular, intrathecal, intravaginal, intravitreal, intrauterine, intra-lesional administration, lymph node administration, intratumoral administration and administration to a mucous membrane of the subject, wherein the administration is intended to have a local and not a systemic effect. As an example, for the treatment of a cancer described herein, the neuromodulating agent may be administered locally (e.g., intratumorally) in a compound-impregnated substrate such as a wafer, microcassette, or resorbable sponge placed in direct contact with the affected tissue. Alternatively, the neuromodulating agent is infused into the brain or cerebrospinal fluid using standard methods. As yet another example, a pulmonary cancer described herein may be treated, for example, by administering the neuromodulating agent locally by inhalation, e.g., in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide or a nebulizer. A neuromodulating agent for use in the methods described herein can be administered or at the site of a tumor, e.g., intratumorally. In certain embodiments, the agent is administered to a mucous membrane of the subject.

Combination therapy

The neuromodulating agents described herein may be administered in combination with one or more additional therapies (e.g., 1 , 2, 3 or more additional therapeutic agents). The two or more agents can be administered at the same time (e.g., administration of all agents occurs within 10 minutes, 5 minutes, 2 minutes or less). The agents can also be administered simultaneously via co-formulation. The two or more agents can also be administered sequentially, such that the action of the two or more agents overlaps and their combined effect is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two or more treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, local routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination can be administered locally in a compound-impregnated microcassette. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 1 1 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 1 8 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after the second therapeutic agent.

For use in treating cancer, the second agent may be a checkpoint inhibitor, a chemotherapeutic drug, a biologic drug. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In other embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In other embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti- CTLA4 antibody such as ipilimumab or tremelimumab). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab;

pembrolizumab; pidilizumab/CT-01 1 ). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736;

MSB0010718C; BMS 936559). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224). In one embodiment, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-1 5049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof. The second agent may also be an anti-angiogenic drug, e.g., an anti-VEGF antibody, or the second agent may be an oncolytic agent e.g., a chemotherapy, a drug that targets cancer metabolism, an antibody that marks a cancer cell surface for destruction, e.g., rituximab or trastuzumab an antibody-drug conjugate, e.g., trastuzumab emtansine, a cell therapy, or other commonly-used anti-neoplastic agent. Dosing

Subjects that can be treated as described herein are subjects with cancer or at risk of developing cancer. The cancer may be a primary tumor or a metastasized tumor. Subjects who can be treated with the methods disclosed herein include subjects who have had one or more tumors resected, received chemotherapy or other pharmacological treatment for the cancer, received radiation therapy, and/or received other therapy for the cancer. Subjects who have never previously been treated for cancer can also be treated using the methods described herein.

In some embodiments, the agent is administered in an amount and for a time effective to result in one of (or more, e.g., 2 or more, 3 or more, 4 or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, (i) increased progression free survival of subject. The methods described herein may include a step of selecting a treatment for a patient. The method includes (a) identifying (e.g., diagnosing) a patient who has cancer or is at risk of developing cancer, and (b) selecting a neuromodulating agent, e.g., a neuromodulating agent described herein, to treat the condition in the patient. In some embodiments, the method includes administering the selected treatment to the subject. In some embodiments, a patient is identified as having cancer based on imaging (e.g., MRI, CT, or PET scan), biopsy, or blood sample (e.g., detection of blood antigen markers, circulating tumor DNA (e.g., by PCR). In some embodiments, a patient is identified as having cancer after presenting with one or more symptoms of a paraneoplastic syndrome (e.g., fever, auto-antibodies directed against nervous system proteins, ataxia, dizziness, nystagmus, difficulty swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech memory loss, vision loss, sleep disturbances, dementia, seizures, dysgeusia, cachexia, anemia, itching, or sensory loss in the limbs). In some embodiments, a patient presents with symptoms of paraneoplastic syndrome and is then identified as having cancer based on imaging (e.g., CT, MRI, or PET scans).

The method may also include (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the neoplasm for innervation, and (c) selecting a neuromodulating agent (e.g., a neuromodulating agent described herein) to treat the patient if the neoplasm is highly innervated (e.g., if the level of innervation is at least 10% higher (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80% higher) than the level of innervation in control tissue, e.g., non-cancerous tissue of the same subject). Innervation may be measured by staining tissue sections for neural markers e.g., immuno-histochemical staining for tyrosine hydroxylase, vesicular acetylcholine transporter; NGF-lnducible Large External glycoprotein, choline acetyltransferase, parvalbumin, neurofilament protein, Synapsin, synaptophysin, NeuN, NSE, MAP2, Beta III tubulin, 160 kD Neurofilament medium/200 kD Neurofilament Heavy, NSE, PSD93/PSD95, Doublecortin (DCX), c-fos, PSA-NCAM, NeuroD or Beta2, Tau, Calbindin-D28k, Calretinin, Neurofilament Protein (NFP), Glial fibrillary acidic protein (GFAP), S100p, Vimentin and CNPase; or by staining tissue sections with cell-identifying stains, e.g., H&E stain, Nissl Stain, Cresyl violet, Neutral red, Thionine and Toluidine blue, Luxol Fast blue stain, Weigert's Chromium hematoxylin method, Page's iron-eriochrome cyanine R, Dextran Conjugates (Fluorescein, Tetramethylrhodamine, Texas Red, Rhodamine Green), Hydrazides & Biocytins, Isolectin GS-IB4 conjugates, Golgi silver stain, or myelin stain; or by imaging the nervous system, e.g., by MRI, CT, PET, EEG, EMG, Myelogram, or magnetoencephalography. In some embodiments, the neoplasm is selected from: head and neck squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, rhabdomyosarcoma, biliary tract cancer, gastric cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, skin cancer (e.g., melanoma), renal cell carcinoma, or colorectal cancer. In some embodiments, the cancer is a cancer listed in Table 10. In some embodiments, the neoplasm is derived from a secretory tissue, glandular tissue, or endocrine or hormonal tissue.

In one embodiment, the method includes (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the neoplasm for perineural invasion, and (c) selecting a

neuromodulating agent to treat the patient if the neoplasm exhibits perineural invasion. In some embodiments, the neoplasm is selected from: head and neck squamous cell carcinoma, adenoid cystic carcinoma, lymphoma, rhabdomyosarcoma, biliary tract cancer, gastric cancer, pancreatic cancer, and prostate cancer. In one embodiment, the method includes (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating the subject for metastasis to brain or spinal cord, and (c) selecting a neuromodulating agent to treat the patient if the neoplasm exhibits metastasis to brain or spinal cord. In some embodiments, the neoplasm is a lung cancer, breast cancer, skin cancer (e.g., melanoma), lymphoma, renal cell carcinoma, Gl tract cancer, prostate cancer, or colorectal cancer.

In some embodiments, the method includes administering the selected treatment to the subject. The method may also include a step of assessing the subject for a parameter of cancer progression or remission, e.g., assessing the subject for one or more (e.g., 2 or more, 3 or more, 4 or more) of: primary tumor size (e.g., by imaging), number of metastases (e.g., by imaging or biopsy), cell death in situ (e.g., by biopsy), blood antigen markers (e.g., by ELISA), circulating tumor DNA (e.g., by PCR), or function of the affected organ (e.g., by a test of circulating enzymes for liver, albuminuria for kidney, lung capacity for lung, etc.).

The method can also include (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating (e.g., profiling) the neoplasm for neurome gene expression, and (c) identifying the patient as having neuro-dependent cancer if one or more neurome genes are expressed by the neoplasm. In some embodiments, the method includes selecting a neuromodulating agent to treat the patient based on neurome gene expression.

The method can also include (a) identifying (e.g., diagnosing) a patient who has a neoplasm, (b) optionally evaluating (e.g., profiling) the neoplasm for neurome gene expression, and (c) selecting a neuromodulating agent to treat the patient based on the neurome gene that is over- or under-expressed. In some embodiments, the neoplasm overexpresses one or more neurome genes. For example, the neoplasm can be a cancer listed in Table 12 that overexpresses a corresponding gene in Table 12. In some embodiments, the neoplasm underexpreses one or more neurome genes. For example, the neoplasm can be a cancer listed in Table 13 that under-expresses a corresponding gene in Table 13. In some embodiments, the neoplasm can be placed into a group (e.g., neurotaxonomic group) based on profiling results. In some embodiments, the neoplasm can be placed into one of four groups based on neurome gene expression: (family 1 ) HTR1 D, ADRA2A, CHRNA7; (family 2) ADRA2C, CHRM3; (family 3) GRM8, DRD2, CHRNB2, CHRM4; (family 4) ADRAB2, ADRA1 B. In some embodiments, the neoplasm co-expresses one or more genes encoding a neuropeptide or neurotransmitter, or a gene necessary for the biosynthesis or recycling of a neuropeptide or neurotransmitter, and one or more genes encoding the cognate neurotransmitter or neuropeptide receptor. For example, the neoplasm can be a cancer listed in Tables 14A-14C that expresses the corresponding biosynthetic enzyme and cognate receptor shown in Tables 14A-14C. In some embodiments, the neuro-dependent tumor expresses one or more neurotrophic factors.

The methods described herein can include profiling a tumor sample to determine whether it expresses one or more neurome genes (e.g., a neurome gene in Table 7 or Table 8 (e.g., a biosynthesis, channel, transporter, ligand, receptor, signaling, synaptic, structural, or vesicular gene)). Profiling results can also be used to categorize (e.g., identify) a tumor as belonging to a neurological taxon (e.g., a neurotaxonomic group). In some embodiments, the neoplasm is placed into a group (e.g.,

neurotaxonomic group) based on profiling results. Placement within a neurotaxonomic group can be used to determine patient treatment (e.g., to determine which neuromodulating agent to administer to the patient). Profiling can be performed using RNA sequencing, microarray analysis, or serial analysis of gene expression (SAGE). Other techniques that can be used to assess gene expression include quantitative RT-PCR. Profiling results can be confirmed using methods such as immunohistochemistry, western blot analysis, or southern blot analysis. Profiling results can be used to determine which neuromodulating agent should be administered to treat the patient. In some embodiments, the methods described herein include selecting a neuromodulating agent based on the neurome gene expression profile of the tumor. For example, if a tumor expresses a neurotransmitter or neurotransmitter receptor, the neuromodulating agent can be a neurotransmission modulator or a neurome gene expression modulator. If a tumor expresses a neuropeptide or neuropeptide receptor, the neuromodulating agent can be a neuropeptide signaling modulator or a neurome gene expression modulator. If a tumor expresses a neuronal growth factor, the neuromodulating agent can be a neuronal growth factor modulator or a neurome gene expression modulator. Neuromodulating agents that decrease expression or activity can be used if the neurome gene is overexpressed, and neuromodulating agents that increase expression or activity can be used if the neurome gene is under-expressed.

Over- and under-expression can be determined by comparing expression of a neurome gene to a housekeeping gene. If the neurome gene is expressed at a higher level than the housekeeping gene (e.g., neurome gene expression is at least 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold higher than

housekeeping gene expression), the neurome gene is overexpressed. In some embodiments, the overexpressed neurome gene is a gene in Table 12 that is expressed in a corresponding cancer in Table 12. If the neurome gene is expressed at a lower level than the housekeeping gene (e.g., neurome gene expression is at least 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold lower than housekeeping gene expression), the neurome gene is under-expressed. In some embodiments, the under-expressed neurome gene is a gene in Table 13 that is under-expressed in a corresponding cancer in Table 13.

In some embodiments, a neuro-dependent tumor is treated with a neuromodulating agent and a second therapeutic agent. The second therapeutic agent can be selected based on tumor type, tumor tissue of origin, tumor stage, or mutations in non-neurome genes expressed by the tumor.

A neuromodulating agent administered according to the methods described herein does not have a direct effect on the central nervous system (CNS) or gut. Any effect on the CNS or gut is reduced compared to the effect observed if the neuromodulating agent is administered directly to the CNS or gut. In some embodiments, direct effects on the CNS or gut are avoided by modifying the neuromodulating agent not to cross the BBB, as described herein above, or administering the agent locally to a subject.

Subjects with cancer or at risk of developing cancer are treated with an effective amount of a neuromodulating agent. The methods described herein also include contacting a tumor or cancer cell with an effective amount of a neuromodulating agent. In some embodiments, an effective amount of a neuromodulating agent is an amount sufficient to increase or decrease tumor innervation or nerve activity in a tumor. In some embodiments, an effective amount of a neuromodulating agent is an amount sufficient to treat the cancer or tumor, cause remission, reduce tumor growth, volume, metastasis, invasion, proliferation, or number, increase cancer cell death, increase time to recurrence, or improve survival.

The neuromodulating agents described herein are administered in an amount (e.g., an effective amount) and for a time sufficient to effect one of the outcomes described above. The neuromodulating agent may be administered once or more than once. The neuromodulating agent may be administered once daily, twice daily, three times daily, once every two days, once weekly, twice weekly, three times weekly, once biweekly, once monthly, once bimonthly, twice a year, or once yearly. Treatment may be discrete (e.g., an injection) or continuous (e.g., treatment via an implant or infusion pump). Subjects may be evaluated for treatment efficacy 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more following administration of a neuromodulating agent depending on the neuromodulating agent and route of administration used for treatment. Depending on the outcome of the evaluation, treatment may be continued or ceased, treatment frequency or dosage may change, or the patient may be treated with a different neuromodulating agent. Subjects may be treated for a discrete period of time (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , or 12 months) or until the disease or condition is alleviated, or treatment may be chronic depending on the severity and nature of the disease or condition being treated.

Kits

The invention also features a kit comprising (a) a unit dose described herein, and (b) instructions for administering the unit dose to treat cancer.

EXAMPLES

The following examples are provided to further illustrate some embodiments of the present invention, but are not intended to limit the scope of the invention; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Example 1 - Screening method for serotonin receptor binders

High throughput methods for identifying compounds from libraries that bind to a target molecule have been described previously, see e.g., Janzen and Bernasconi (Eds.), High Throughput Screening: Methods and Protocols (Methods in Molecular Biology), Humana Press 2009. In brief, to identify compounds that bind to the serotonin receptor 5HT2C the following screening assay is performed:

Cell culture & membrane (target protein) preparation:

AV12 cells are stably transfected with a eukaryotic expression vector containing the coding region for the human 5HT2C receptor (see e.g., Lucaites, V. L, et al., (1996) Life Sci. 59(13), 1081 -

1095). To prepare membrane protein preparations, using the technique of Bosworth and Towers, Nature 341 , 167, 1989, cells are grown to a cell density of 2 - 3 10 ⁶ cells/mL, and 15 L are harvested on a daily basis by centrifugation, washed in phosphate-buffered saline (PBS), and stored as frozen cell pastes at - 80°C. To loosen the frozen cell paste, 30 mL of 50 mM Tris-HCI, pH 7.4, at ambient temperature are added to 7.5 grams of pellet. The cell slurry is homogenized on ice in a 55-mL glass/teflon dounce, transferred to a 250-mL conical tube that is then filled to the neck with buffer, mixed, and centrifuged in a table top centrifuge at 200g (1060 RPM, GH-3.7 rotor) at 4°C for 15 min. The supernatant is collected and saved on ice. The pellet is resuspended and subjected to the homogenization and centrifugation procedure just described. The 200g supernatant is again collected and combined with the first supernatant stored on ice. The combined supernatants are then centrifuged at 14,250 rpm in a Sorvall RC5 centrifuge (GSA SLA-1500 rotor) for 50 min at 4°C. The supernatant is gently removed and discarded, and the remaining membrane pellet is resuspended using the dounce homogenizer. The membrane protein concentration is determined (BCA kit) and aliquots of the membrane preparation are quick frozen in liquid nitrogen and stored at -80°C. The average yield is 1 .2% of starting weight. SPA-format receptor-binding assay:

Twenty microliter of test compound, unlabeled 5-HT control, or assay buffer is added to each well of a 96-well microtiter plate. Fifty microliter of 15-nM [3H]-5HT ligand (5-Hydroxy(3H)tryptamine trifluoroacetate (Code TRK1006 Amersham) at a final concentration of 5 nM/well) is then added to the wells followed by 80 μΙ_ (20 ug) of 5HT2C membranes as prepared above and the plates are shaken for 1 min. After a 30-min incubation at room temperature, 0.5 mg of Wheat Germ Agglutinin (WGA)-SPA beads (Amersham biotech) are added, plates are mixed by shaking every 30 min for 2 h and then counted in a MicroBeta Scintillation Counter (Perkin Elemer Wallac). The absence of binding of labeled 5HT ligand in a sample indicates that the test compound has successfully bound the target receptor. Test compounds that bind target receptor with greater than 100 nM EC50 (p<0.05 for at least 3 replicates) are selected for further testing.

Example 2 - Dose finding study for neuromodulator candidate

A lead candidate for treatment of a solid cancer is identified by the screening method of Example 1 . Based on preclinical data from in vitro and in vivo testing of the identified lead compound, it is determined that 120 mg is a safe starting dose in humans.

A '3+3' design of incremental escalation of dose in a cohort of subjects is employed to identify a Maximum Tolerated Dose (MTD) of the lead candidate. Dose escalation is determined using a Fibonacci sequence, whereby an additional 100% of the original dose is administered for the second time, 67% of the second dose for the third time, and so on, until the MTD is reached.

Three patients are given 120 mg of the identified lead compound. If none of the three patients report any dose limiting toxicity (DLT) of this first dose, then the dose is escalated for the next cohort of 3 subjects. If within any one particular cohort one of the patients reports a DLT, the study at that dose is repeated. If two of the patients report DLT, this dose is then regarded as the Maximum Tolerated Dose (MTD).

Example 3 - Inhibition of cancer cell growth in 2D culture

The agents selected as described in Example 1 are subjected to testing for cell proliferation.

A way to measure cell proliferation is to detect an antigen present in proliferating cells, but not nonproliferating cells, using a monoclonal antibody to the antigen. For example, in human cells, the antibody Ki-67 recognizes the protein of the same name, expressed during the S, G2 and M phases of the cell cycle but not during the GO and G1 (nonproliferative) phases. Reagents and solutions can be purchased commercially, e.g., Muse system from Millipore. The following procedure is used:

Culture cells, including for positive and negative controls, in appropriate culture medium. Wash cell samples once with PBS, then transfer 5 x 10 ^Λ 3 - 1 x 10 ^Λ 5 cells per sample into each tube. Prepare 1 X Fixation Solution (50 μΙ_ per test) and 1 X Assay Buffer (500 μΙ_ per test). Add 50 μΙ_ of 1 X Fixation Solution to each tube. Mix and incubate for 1 5 minutes at room temperature. Add 150 μΙ_ of 1 X Assay Buffer, centrifuge, and remove supernatant. Add 100 μΙ_ of Permeabilization Solution to each tube. Mix and incubate for 15 minutes at room temperature. Add 100 μΙ_ of 1 X Assay Buffer, centrifuge, and remove supernatant. Add 50 μΙ_ of 1 X Assay Buffer to each tube. Mix and incubate for 15 minutes at room temperature. Add 10 μΙ_ of either Hu lgG1 -PE isotype control or Hu Ki67-PE Antibody to each tube. Mix and incubate for 30 minutes at room temperature. Add 150 μΙ_ of 1 X Assay Buffer to each tube and analyze by flow cytometry. Binding of anti-Ki67 detected by flow cytometry indicates that the agent causes proliferation.

Example 4 - Treatment of prostate cancer with a neuromodulating agent

A patient diagnosed with prostate cancer is treated locally with an antibody specific for ProNGF

(nerve growth factor precursor). In a surgical approach, depending on the age and preference of the patient, either a general or local anesthetic is administered. If a general anesthetic is administered, the patient is intubated. The surgical approach may differ according to surgeon preference and patient characteristics, however it may include, but will not be limited to open retro-pubic (incision in lower abdomen), open perineal (incision in perineum) or laparoscopic approaches. After initial incision and dissection through the abdominal or perineal muscles, a surgical window is established, and the treatment involves administration of the antibody either intra-tumorally and/or towards the innervating structures of the prostate gland and/or tumor, including above and below the plexuses formed by the parasympathetic, visceral, efferent, and pre-ganglionic fibers that arise from the sacral levels (S2-S4) and the sympathetic fibers from the thoracolumbar levels (L1 -L2). A drainage tube may be inserted into the bladder and kept in place for a period of up to 10 days following the surgery. Furthermore, a catheter may be placed inside the patient for continuous administration of the previously described compounds, for a time period after surgery. If intubated, patient is extubated and may be started on antibiotics.

A minimally invasive approach to local administration of drug may involve a transurethral approach, whereby, a catheter or other such device is passed through the urethra and placed in proximity to the prostate gland. The antibody is then administered through this catheter.

In a non-surgical approach, the antibody is administered intravenously. For intravenous administration, access to a vein is established through an intravenous cannula. If this is not possible, due to factors such as vasospasm of vessels or poorly accessible veins, a central venous catheter is employed. Once intravascular access is established, the previously described compound will be administered.

Following treatment, the patient's peripheral blood is specifically tested for Prostate Specific Antigen (PSA) levels. Active monitoring of PSA levels is carried out every 3 months for 2 years, after which, measurement of PSA levels may be extended to once every 6 months, depending on the discretion of the health care professional.

Example 5 - Identification of novel neurobiological correlations with cancer

To identify novel correlations of neurobiological signaling molecules and cancer cells, a list of neurotransmitter and neuropeptide genes and pathways was generated using a survey of published literature and UniProt (Table 1 ). These genes and pathways identified were used as inputs to publicly available cancer databases (e.g., Cancer Cell Line Encyclopedia). Through the bioinformatics analysis, novel correlations were found of overexpression by at least two-fold of certain neurobiological signaling genes of interest in certain individual cancer cell lines. Table 10 lists the neurobiological signaling molecules (column 1 ) that are targets for therapeutic intervention for such correlated cancers (column 2).

TABLE 10: CANCER TARGETS

Accession

Gene Cancer

Number

Adrbk2 Lymphoma - Burkitt P35626

Adrbk2 lymphoma - DLBCL P35626

Adrbk2 Lymphoma -other P35626

Chrm3 esophagus P20309

Chrm3 multiple myeloma P20309

Chrna6 Lymphoma - Burkitt Q15825

Lymphoma -

Chrna6 Q15825

hodgkin

Chrna5 neuroblastoma P30532

Chrna9 Leuk. T cell ALL Q9UGM1

Chrna9 Melanoma Q9UGM1

Chrnbl Leuk. B cell ALL P1 1230

Chrnbl Leuk. T cell ALL P1 1230

Chrnb4 neuroblastoma P30926

Chrng Meningioma P07510

ADCYAP1 R1 neuroblastoma P41 586

C4orf48 Leukemia - other Q5BLP8

C4orf48 Lymphoma - Burkitt Q5BLP8

CALCB Ewings Sarcoma P10092

CALCB lung - small cell P10092

CALCB neuroblastoma P10092

CCK Chondrosarcoma P06307

CCK Ewings Sarcoma P06307 Accession

Gene Cancer

Number

CPE Leuk. AML P16870

CPE Leuk. B cell ALL P16870

CPE Leuk. CML P16870

CPE Leuk. T cell ALL P16870

CPE lung - small cell P16870

CPE Lymphoma - Burkitt P16870

CPE lymphoma - DLBCL P16870

Lymphoma -

CPE P16870

hodgkin

CPE Lymphoma -other P16870

CPE multiple myeloma P16870

CPE Prostate P16870

CPE neuroblastoma P16870

CRHBP lymphoma - DLBCL P24387

CYSLTR1 Ewings Sarcoma Q9Y271

CYSLTR1 Leuk. AML Q9Y271

CYSLTR1 Leuk. B cell ALL Q9Y271

CYSLTR1 Leuk. CML Q9Y271

CYSLTR1 Leukemia - other Q9Y271

CYSLTR1 Lymphoma - Burkitt Q9Y271

CYSLTR1 lymphoma - DLBCL Q9Y271

CYSLTR1 Lymphoma -other Q9Y271

CYSLTR1 multiple myeloma Q9Y271 Accession

Gene Cancer

Number

FOLH1 Melanoma Q04609

FOLH1 Prostate Q04609

GAL Colorectal P22466

GAL esophagus P22466

GAL Leuk. CML P22466

GAL mesothelioma P22466

GAL Prostate P22466

GAL neuroblastoma P22466

GALR3 Meningioma 060755

GRP Ewings Sarcoma P1 1 021

GRP lung - small cell P1 1 021

KISS1 R Leuk. CML Q969F8

KISS1 R Leuk. CML Q969F8

KISS1 R Prostate Q969F8

KISS1 R multiple myeloma Q969F8

LTB4R esophagus Q15722

LTB4R Leuk. AML Q15722

LTB4R Leuk. T cell ALL Q15722

LTB4R Leukemia - other Q15722

LTB4R Lymphoma - Burkitt Q15722

LTB4R lymphoma - DLBCL Q15722

LTB4R Lymphoma -other Q15722

MRGPRF Meningioma Q96AM1 Accession

Gene Cancer

Number

MRGPRF mesothelioma Q96AM1

MRGPRF osteosarcoma Q96AM1

NMU Colorectal P48645

NMU Endometrium P48645

NMU Ewings Sarcoma P48645

NMU Leuk. AML P48645

NMU Leuk. B cell ALL P48645

NMU Leuk. T cell ALL P48645

NMU lung - small cell P48645

NMU Lymphoma - Burkitt P48645

NMU lymphoma - DLBCL P48645

NMU Lymphoma -other P48645

NMU Melanoma P48645

NMU multiple myeloma P48645

NMU osteosarcoma P48645

NMU Ovary P48645

NMU pancreas P48645

NMU prostate P48645

NMU Soft tissue P48645

NMU upper aerodigestive P48645

NPB Leukemia - other Q8NG41

NPBWR1 Meningioma P48145

NPW Ewings Sarcoma Q8N729 Accession

Gene Cancer

Number

NPW Leukemia - other Q8N729

NPW Leukemia - other Q8N729

NPY Ewings Sarcoma P01303

NPY Leuk. B cell ALL P01303

NPY neuroblastoma P01303

NPY5R Ewings Sarcoma Q15761

NTS esophagus Q6FH20

NTS Ewings Sarcoma Q6FH20

NTS lung - small cell Q6FH20

NTS neuroblastoma Q6FH20

NTSR1 Meningioma P30989

NXPH2 Ewings Sarcoma 095156

PENK Ewings Sarcoma P0121 1

PENK osteosarcoma P0121 1

PNOC Ewings Sarcoma Q1351 9

PNOC Lymphoma - Burkitt Q1351 9

PNOC lymphoma - DLBCL Q1351 9

PNOC Lymphoma -other Q1351 9

PNOC multiple myeloma Q1351 9

PROK2 Ewings Sarcoma Q9HC23

PROK2 Leuk. AML Q9HC23

PROK2 Leuk. CML Q9HC23

PTH2R Leuk. AML Q9Y3E5 Accession

Gene Cancer

Number

PTH2R Leuk. CML Q9Y3E5

PTH2R neuroblastoma Q9Y3E5

RLN2 lung - small cell P04090

RLN2 Lymphoma - Burkitt P04090

RLN2 pancreas P04090

RLN2 prostate P04090

SCG2 Chondrosarcoma P13521

SCG2 Ewings Sarcoma P13521

SCG2 Glioma P13521

SCG2 lung - small cell P13521

SCG2 Medulloblastoma P13521

SCG2 Melanoma P13521

SCG2 Soft Tissue P13521

SCG2 Thyroid P13521

SCG2 Meningioma P13521

SCG3 lung - small cell Q8WD2

SCG3 Medulloblastoma Q8WD2

SCG5 Chondrosarcoma P05408

SCG5 Glioma P05408

SCG5 Kidney P05408

SCG5 Thyroid P05408

SCG5 lung - small cell P05408

SCG5 mesothelioma P05408 Accession

Gene Cancer

Number

SCG5 neuroblastoma P05408

SORCS1 Melanoma Q8WY21

SORCS2 Chondrosarcoma Q96PQ0

SORCS2 Upper aerodigestive Q96PQ0

SORCS2 Medulloblastoma Q96PQ0

SSTR1 Mesothelioma P30872

SSTR2 Medulloblastoma P30874

SSTR2 Neuroblastoma P30874

UCN2 Melanoma Q96RP3

UTS2 bile duct 095399

UTS2 Ewings Sarcoma 095399

UTS2 Leuk. AML 095399

VIP Neuroblastoma P01282

VIPR1 bile duct P32241

VIPR1 Colorectal P32241

VIPR1 Pancreas P32241

Htr2c Esophagus P28335

Example 6 - Neuromodulating agents affect cancer cell growth

Cancer cell lines were grown in appropriate cell culture medium. On day 0, cells were plated in black organogenix nanocult 96-well plates with low-bind honeycomb pattern. Cells were plated in a low serum medium to increase the dynamic range observable for growth promotion. Within three days spheroids were visible.

On day 1 post plating, compounds were added at a range of doses to the cells, between mid- nanomolar and low micromolar, spanning at least a 1 0Ox dose range. On day 4 post plating, number of cells are quantified by staining with Cell Titer Glo and reading on a plate reader.

We observed that adenosine at 10-200 μΜ enhances the growth of multiple pancreatic cancer cell lines (CFPAC, PANC-1 , PL45, ASPC-1 , CAPAN-1 , CAPAN-2) by at least 10% increased signal over 24 hours than untreated cells. Upon follow-up of the adenosine pathway, we performed a similar assay with chemical antagonists of adenosine receptors at a range of concentrations between 1 0 nM - 1 0 uM. We found that the Adenosine Receptor 1 (A1 R) antagonist KW3902 inhibited the growth of BXPC3 pancreatic cancer cells and NCI-H82 small cell lung cancer cells at low micromolar concentration (FIGS. 1 A-1 B). We also found that the Adenosine Receptor 3 (A3R) antagonist MRS-1220 inhibited the growth of NCI-H82 small cell lung cancer cells at low micromolar concentration (FIG . 1 C).

We observed that histamine and the synthetic agonists 2-pyridylethylamine (H1 receptor), amthamine (H2 receptor), R-(-)-alpha-methylhistamine (H3 receptor), and VUF 1 0460 (H4 receptor) increase the growth rate of the pancreatic cancer cell lines PANC-1 , PL45, ASPC-1 , and CAPAN-2 by at least 5% compared to untreated control . These data suggest that inhibition of the histamine receptor signaling pathway and antagonism of the adenosine receptor signaling pathway inhibit cancer growth and can be a useful therapeutic for patients with pancreatic cancer, lung cancer, or other cancers that express these receptors. Example 7 - Treatment of a patient with small cell lung cancer with adenosine antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g. , small cell lung cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression . To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases adenosine signaling (e.g. , an adenosine antagonist, such as MRS-1220, MRS-1334, MRS-1 523, MRS-3777, MRE3008F20, PSB-1 0, PSB-1 1 , and VUF-5574). MRS-1 220 is administered orally to decrease cancer growth. MRS-1220 is administered in a therapeutically effective amount, such as from 1 0 μg/kg to 500 mg/kg (e.g., 1 0 μg/kg, 1 00 μg/kg, 500 μg/kg, 1 mg/kg, 1 0 mg/kg, 50 mg/kg, 1 00 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, MRS-1220 is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g. , 1 , 2, 3, 4, 5, 6, or 7 times a week or more). MRS-1220 is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 1 0% or more (e.g., 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g. , digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of MRS-1 220 can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of MRS-1220. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that MRS-1220 has successfully treated the cancer.

Example 8 - Treatment of a patient with pancreatic cancer with histamine antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g. , pancreatic cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression . To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases histamine signaling (e.g. , a histamine Hi receptor antagonist, such as acrivastine, azelastine, astemizole, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, and cetirizine). The histamine receptor antagonist is administered locally (e.g., injected intratumorally) to decrease cancer growth. The histamine receptor antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, The histamine receptor antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more). The histamine receptor antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the histamine receptor antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the histamine receptor antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the histamine receptor antagonist has successfully treated the cancer.

Example 9 - Orthotopic MIAPACA2 pancreatic cancer treated with Haloperidol

Cell culture

MIAPaCa2 Flue cells were grown in DMEM tissue culture media with 10% fetal calf serum, 2.5% Horse Serum, 1 % penicillin/streptomycin and Puromycin (20 ug/mL). On the day of implantation, cells were washed in PBS, trypsinized and resuspended at a density of 2 x 10 ⁶ cells/ml in a Matrigel solution prior to being implanted into the pancreas a volume of 0.05 mL using a 25G needle.

Mice

Nude mice (Nu/Nu) were anesthetized and the pancreas exposed via peritoneal incision and physical displacement of the spleen. Cells were injected into the pancreas in a total volume of 0.05 mL and the surgical wound closed with VetBond. Bioluminescence was assessed by administration of D- luciferin and imaging on an IVIS system. Mice with leakage of bioluminescent signal immediately after surgery were removed from study. Mice were randomized into groups of equal mean bioluminescence approximately 14 days post-implant.

Drug dosing

Haloperidol, an agent that blocks a variety of dopamine receptors and is used in the treatment of psychiatric disorders in humans, was administered daily IP in a solution of 0.85% lactic acid and 0.5% Cremophor EL. One group of mice received haloperidol alone, a second group received gemcitabine chemotherapy (the standard of care for human pancreatic cancer treatment), and a third group received a combination of haloperidol and gemcitabine. For groups also receiving gemcitabine, gemcitabine was dosed 50 mg/kg IP daily. Tumor growth was determined bi-weekly with bioluminescent measurement. End of Study

The study was terminated three weeks after initiation of drug dosing. At termination, mice were sacrificed and pancreas collected and weighed.

As shown in FIG. 2, mice that received Haldol saw a -50% reduction in tumor weight at the end of study (150 mg vs 300 mg for the vehicle-treated group). This reduction was equivalent to the reduction observed in the gemcitabine treated group. The combination treated group showed a reduction of tumor weight by about 67% compared to the vehicle-treated control group (200 mg vs 300 mg).

These data suggest that patients with pancreatic cancer that express dopamine receptor may be candidates for treatment with a dopaminergic antagonist, and that this pathway antagonism may result in reduced tumor growth and better outcomes. The dopaminergic antagonist may act by an orthogonal mechanism to standard chemotherapy, thus opening up this treatment to patients who have been previously treated with chemotherapy.

Example 10 - Pancreatic cancer treatment using a dopamine antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., pancreatic cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases dopamine signaling (e.g., a dopamine antagonist, such as haloperidol, paliperidone, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, amoxapine, clomipramine, and trimipramine). The dopamine antagonist can be administered at a dose lower or higher than that administered to a patient with a neuropsychiatric disorder, or it can be chemically modified (e.g., PEGylated), delivered in a particulate formulation (e.g., a nanoparticle or microparticle), or injected into the pancreatic tumor so that it does not cross the blood brain barrier. The dopamine antagonist is administered locally (e.g., injected intratumorally) to decrease cancer growth. The dopamine antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, The dopamine antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more). The dopamine antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the dopamine antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the dopamine antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the dopamine antagonist has successfully treated the cancer. Example 11 - Treatment of a subcutaneous tumor (SCLC PDX) using an implanted microcassette Small cell lung cancer cells derived from a human donor (CrownBio, San Diego CA) were injected subcutaneously into the flanks of nude mice. Tumors were grown to a size of approximately 6-1 0 mm before device implantation.

Microdose drug delivery devices were manufactured as described in Jonas et al., Sci. Transl. Med. 7, 284ra57 (2015). Briefly, cylindrical, micro-scale devices with 0.82 (diameter) x4 mm (length) were manufactured from medical-grade Delrin acetyl resin blocks (DuPont) by micromachining (CNC Micromachining Center, Cameron). Circular reservoirs were shaped on the outer surface of devices in dimensions of 230 um (diameter) χ 250 um (depth). Drug-polymer mixtures were packed into device reservoirs using a tapered, metal needle (Electron Microscopy Sciences) until the reservoirs were completely filled.

Devices were implanted directly into the mouse tumor using a 19-gauge spinal biopsy needle (Angiotech) and a retractable needle obturator to push the device into the tissue. Devices containing the drugs remained in situ for 24 hours.

The flank tumor was excised and the tissue containing the device was fixed for 24 hours in 10% formalin and perfused with paraffin. This specimen was sectioned using a standard microtome and tissue sections were collected from each reservoir. Sections were antibody-stained by standard

immunohistochemistry using antibodies against cleaved-caspase-3 (CC3), KI-67, and phospho-AKT (Cell Signaling) and scored using an ImageJ image (v1 .48) analysis algorithm in a blinded manner.

When the tumors were analyzed (FIG. 3), patient-derived xenograft tumors from patient 5197 that had been exposed to the reservoir containing the dopaminergic receptor DRD2 antagonist L-741 ,626, showed a dose-dependent killing as measured by CC3 positive tissue with a clear gradient away from the reservoir. The same sample showed a negative gradient for phospho-AKT indicating that the L-741 ,626 was inhibiting signaling via dopamine receptor, as AKT is downstream of DRD2. The same tumor exposed to cisplatin chemotherapy showed minimal cell killing, suggesting that dopaminergic antagonism is killing the cells by an independent mechanism. Interestingly, patient-derived xenograft tumors from patient 521 7 that expresses ~1 Ox lower levels of DRD2 mRNA compared to patient 5197 were not impacted at all by treatment with the L-741 ,626 dopaminergic antagonist, suggesting again that the effect is mediated by signaling through dopamine receptor.

These data suggest that a patient whose tumor expresses a neurological gene signature with modulators of the activated neurological pathway may be a good candidate for treatment with a drug that targets the active neurological pathway in the tumor.

Example 12 - Treatment of SCLC using a dopamine antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., small cell lung cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a neuromodulating agent based on neurome gene expression in a biopsy. For example, a biopsy can be collected from a patient with small cell lung cancer and assayed for expression of a dopamine receptor using quantitative RT-PCR (qPCR), western blot analysis, immunohistochemistry, or ELISA. The expression of the dopamine receptor can be compared to the expression of a housekeeping gene, and a tumor with a higher relative expression of a dopamine receptor (e.g., 1 .5, 2, 2.5, 3, 4, 5, or 1 0 or more fold higher relative expression of a dopamine receptor compared to a housekeeping gene) will be considered positive for expression of a dopamine receptor. A patient with such a tumor can be treated with a dopamine receptor antagonist. To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases dopamine signaling (e.g., a dopamine antagonist, such as haloperidol, L-741 ,626, paliperidone, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, amoxapine, clomipramine, and trimipramine). The dopamine antagonist can be administered at a dose lower or higher than that administered to a patient with a neuropsychiatric disorder, or it can be chemically modified (e.g., PEGylated), delivered in a particulate formulation (e.g., a nanoparticle or microparticle), conjugated to a targeting moiety, or administered locally so that it does not cross the blood brain barrier.

The dopamine antagonist is administered locally (e.g., injected intratumorally) to decrease cancer growth. The dopamine antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, The dopamine antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more). The dopamine antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the dopamine antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the dopamine antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the dopamine antagonist has successfully treated the cancer.

Example 13 - Intratumoral injection of Botox to prevent gastric tumor initiation

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer or at risk of developing cancer (e.g., gastric cancer), so as to inhibit cancer growth, reduce tumor burden, or prevent tumor initiation. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment based on a genetic predisposition for developing cancer (e.g., mutations in CDH1 , CTNNA1 , DOT1 L, FBX024, PRSS1 , MAP3K6, MSR1 , or INSR for gastric cancer, see Petrovchich et al., Semin oncol 43:554 (2016)). To treat the patient, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases neurotransmission (e.g., a neurotoxin such as botulinum toxin, tetanus toxin, tetrodotoxin, or conotoxin). The neurotoxin (e.g., botulinum toxin A (Botox)) is administered locally (e.g., injected into the wall of the stomach). The dose of Botox administered is 200 U in a 2 ml_ volume, with higher or lower doses administered depending on tumor burden (e.g., higher doses can be administered to patients with larger or later stage tumors, while lower doses can be administered to prevent tumor initiation in patients with genetic mutations who have not yet developed cancer). In some embodiments, Botox is administered, twice a year, once every four months, bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more).

Botox is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, prevent tumor initiation, or decrease neurotransmission by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Botox efficacy can be assessed by evaluating a biopsy sample of the patient's stomach wall for a reduction in electrical activity (e.g., using in vitro electrophysiological recording), or by evaluating the presence of cleaved SNARE proteins (the molecular target of Botox) using ELISA. Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). In patients at risk for developing cancer, gastric tissue biopsies can be compared before and after Botox administration to determine if the epithelial layers of the stomach are less neoplastic by histology. Images from before and after administration of Botox can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of Botox. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, or growth of tumors, or stomach tissue that appears less neoplastic indicates that Botox has successfully treated the cancer or reduced the likelihood or prolonged the development of cancer.

Example 14 - Targeting neurons in pancreatic cancer using a viral vector encoding a neurotoxin According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., pancreatic cancer), so as to inhibit cancer growth, reduce tumor burden, or prevent tumor initiation. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment based on tumor innervation (e.g., based on a histological analysis of a tumor biopsy from the patient using neuron-specific antibodies such as anti-Neurofilament and anti- PGP9.5 to detect the presence of nerves). To treat a patient, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases neurotransmission (e.g., a neurotoxin such as botulinum toxin, tetanus toxin, tetrodotoxin, or conotoxin). A gene encoding tetanus toxin (e.g., TeNT, UniProt P04958) can be encoded in a replication-deficient herpes virus, as described in Burton et al., DNA & Cell Biology 21 :915 (2002). For additional specificity, TeNT gene expression can be driven by a neuron-specific promoter, such as the synapsin promoter. The genetically modified herpes viral vector can be prepared for injection in bolus doses of 1 x10 ^Λ 1 1 particles per dose. The viral vector encoding a neurotoxin can be administered in combination with other cancer treatments, such as chemotherapeutic agents.

The patient can be started on a standard treatment of Gemcitabine intravenously at a dose of 1000 mg/m ² + nab-paclitaxel 125 mg/m ² as per hospital standards. One cycle will be one dose of

Gemcitabine + nab-paclitaxel given on days 1 , 8, and 15 of a 28 day cycle. The TeNT-encoding herpes viral vector can be administered by intratumoral injection every other week for 6 doses starting on day 1 5 of the first cycle of chemotherapy. The most common route of injection is ultrasound-guided

percutaneous injection, but endoscopic ultrasound-guidance can be used for some patients as appropriate. All patients can receive anti-anxiety medication or sedation as needed for comfort during the procedure. The viral vector infects tumor-resident neurons and travels to the dorsal root ganglion where it begins to produce recombinant TeNT. The toxin inhibits neurotransmitter release in the virally- transduced neurons, thus depriving the cancer of functional nerves essential for its survival. Neurotoxin efficacy can be assessed by evaluating a biopsy sample of the patient's tumor for a reduction in electrical activity (e.g., using in vitro electrophysiological recording), or by evaluating the presence of nerves using PGP9.5 or Neurofilament immunohistochemical staining in biopsy tissue sections. Electrical activity or tumor innervation can be reduced by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more) compared to biopsy samples prior to viral vector administration, or compared to biopsy samples from patients treated with chemotherapy alone. Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after treatment can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to

administration of the TeNT-encoding viral vector. Outcomes can also be compared between patients receiving chemotherapy alone and patients receiving combination therapy with the TeNT-encoding viral vector. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, or growth of tumors, or innervation of tumors indicates that the TeNT-encoding viral vector has improved cancer outcomes. Example 15 - Administration of a neurotrophic factor blocking antibody to treat cancer

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient, so as to inhibit tumor growth (e.g., osteosarcoma growth). To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that inhibits

neurogenic/axonogenic signals (e.g., a blocking or inhibitory antibody against a neurotrophic factor, such as NGF, BDNF, ProNGF, Sortilin, TGFp family ligands, GFRa family ligands, CNTF, LIF, neurturin, artemin, persephin, neurotrophin, chemokines, cytokines, and others listed in Table 1 C).

One exemplary antibody that can be used is an anti-NGF sequestering antibody (e.g., mAb 91 1 , Rinat/Pfizer), the CDRs for which are described in Hongo et al., Hybridoma 19:21 5 (2000) and Cattaneo, Curr Opin Mol Ther 12:94 (2010). The anti-NGF antibody can be administered to the patient, for example, by parenteral administration (e.g., intramuscular or intravenous administration) or intratumorally, to inhibit tumor growth. The anti-NGF antibody is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the blocking or inhibitory antibody is administered at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more). The anti- NGF antibody can be administered to the patient in an amount sufficient to inhibit tumor growth or reduce tumor volume. Tumor growth can be assessed using imaging methods (e.g., digital radiography, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). For bone cancer such as osteosarcoma, bone density can be assessed using digital radiography to monitor tumor growth.

Radiograph images of the affected bones are used to evaluate tumor-induced bone destruction by assigning scores of 0-4: 0, normal bone with no signs of destruction; 1 , small radiolucent lesions indicative of bone destruction (1 -3 lesions); 2, increase in the number of lesions (3-6 lesions) and loss of medullary bone; 3, loss of medullary bone and erosion of cortical bone; 4, full-thickness unicortical bone loss. The patient can be evaluated, for instance, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more following administration of the anti-NGF antibody. A finding of the same or a reduced score following administration of the anti-NGF antibody provides an indication that the treatment has successfully inhibited tumor growth.

Example 16 - Colony Formation Assay to test DRD2 inhibition in glioblastoma cell lines

Glioblastoma lines A172, LN-18, T98G, LN-229, U87 MG, and U1 18 MG were passaged in culture per manufacturer's recommendations.

On day 0 of the experiment, cells were plated in 24 well plates at a density of 500 cells per well in triplicate. On day 1 , DRD2 antagonists haloperidol and L741 ,626 were added to the wells at a range of concentrations between 1 μΜ and 20 μΜ. Media was changed every three days. On day 9 of the experiment, cells were fixed with formalin and stained with Cyto60 (a nucleic acid stain). Fluorescence was read on a Licor-Odyssey imager to assess the number of viable cells in the assay.

As shown FIGS. 4A-4B, haloperidol and L741 ,626 were able to reduce the number of glioblastoma cells growing in culture compared to DMSO control in a dose-dependent fashion in the cell lines. The effect was strongest for both agents in A172, LN-1 8, LN 229, and U1 18 cell lines.

These data suggest that dopaminergic antagonism is sufficient to limit the growth of glioma cell lines in culture, suggest that dopamine antagonists could be used to treat patients with glioma.

Example 17 - Treatment of glioma using a dopamine antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., glioma), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. To this end, a physician of skill in the art can administer to the human patient a neuromodulating agent that decreases dopamine signaling (e.g., a dopamine antagonist, such as haloperidol, paliperidone, clozapine, risperidone, olanzapine, quetiapine, ziprasidone, amoxapine, clomipramine, L-741 ,626, and trimipramine). The dopamine antagonist is administered locally (e.g., injected intratumorally) to decrease cancer growth. The dopamine antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, The dopamine antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more). The dopamine antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the dopamine antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the dopamine antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the dopamine antagonist has successfully treated the cancer.

Example 18 - Neuro-dependent cancer is a novel cancer taxonomy

We observed that certain cancers express a gene signature that can be characterized as highly neurological, as defined by genes whose essential function is in the process of neurotransmission (e.g., neurome genes). These genes include neurotransmitter receptors, neuropeptide receptors,

neurotransmitter transporters, neurotransporter biogenesis or biosynthetic genes, ion channels, ion pumps, vesicular proteins, synaptic junction proteins, axonal guidance proteins, neurotrophic factors, structural proteins, transporters, and signaling molecules found downstream of neuronal cell surface receptors (See Complete List in Table 7 and Table 8).

Surprisingly, the neurological gene signature of a tumor did not always correspond with the tissue type of origin. For example, in the heatmap (FIG. 5), 1 152 primary tumors (columns) from human subjects were classified by their RNA expression of 60 different neurotransmitter receptors (rows). The tissue of origin of the tumors is denoted by the colored identifier bar at the top of each column. From this analysis, several neuro-defined groups emerged based on high expression of one or more of the following neurotransmitter receptor genes: (family 1 ) HTR1 D, ADRA2A, CHRNA7; (family 2) ADRA2C, CHRM3; (family 3) GRM8, DRD2, CHRNB2, CHRM4; (family 4) ADRAB2, ADRA1 B.

This phenomenon is amplified for visual effect by performing a principal components analysis, shown in the plot (FIG. 6). Essentially, neurotransmitter gene expression enabled the clustering of tumors into five distinct taxa, as shown in the left dot-plot where each dot represents a tumor type and the shape of the dot corresponds to the neurological taxon. In FIG. 7, the same data is represented but the tumors are displayed according to the tissue of origin. As is evident by inspection, the neurological taxonomy does not correspond to the tissue of origin and thus represents a new taxonomy for classifying tumors.

Deeper analysis of additional data sets supports this novel neurological classification. For example, as shown in FIGS. 8A-8F, our analysis of 276 primary lung cancers by RNA sequencing identified distinct clusters of tumor types based on their (1 ) co-expression of muscarinic receptor CHRM4 and dopamine receptor DRD2, (2) expression of adrenergic receptor ADRB2, or (3) low expression of all three. These graphs show that the neurome gene expression clustering does not correspond to common histological taxonomy. Most small cell lung cancer (SCLC) appear to be CHRM4 and DRD2 high (Group 1 , corresponding to family 3 mentioned above. FIG. 8D), though others are negative (Group 3). Non- small cell lung cancer (NSCLC) samples are distributed into all three groups (FIGS. 8A-8C), with no correlation between squamous cell (SCC) and adenocarcinoma (ADC) subtypes.

This suggests that neurological diversity exists even within tumors that are homogeneously classified as "Lung cancer" according to tissue of origin, histology, or common oncogenic markers.

The implications for this novel neuro-taxonomy are that tumors that display an expression signature of neurome genes may be susceptible to particular interventions targeting these pathways or may be highly dependent on nerve-derived signals and thus responsive to neuro-ablative or

neuromodulatory therapies. Example 19 - Neurome gene overexpression in cancer

One form of cancer neuro-dependence is marked by the overexpression of neurome genes, like neurotransmitter or neuropeptide receptors, synaptic junction proteins, neuronal growth factors, channels, transporter, signaling proteins, or others as listed in Table 7 or Table 8. Tumors that overexpress neurome genes may be more dependent on the signaling or molecular cues that are transmitted by these genes and proteins, and as such, these genes and proteins represent potential vulnerabilities for therapeutic intervention.

Shown in Tables 1 1 A-1 1 D below are gene expression signatures for four different

neurotransmitter receptors across a range of human cancers: Dopamine receptor DRD2, muscarinic receptor CHRM3, adrenergic receptor ADRB2, and adrenergic receptor ADRB3. Each table displays RNAseq data for a particular neurotransmitter in tumor samples from patients with different types of cancer. Gene expression assessed using RNAseq was scored by log2(FPKM). Values >0 are deemed to be "overexpressed" in this assay. The table shows the percentage of the total number of tumors analyzed from each cancer type (N) that overexpress the receptor. What is clear from this data is that multiple cancers across different tissue types express these neurotransmitter receptors. The ADRB3 data shows that this receptor is essentially not expressed across any cancer types, indicating that the patterns of expression for the other receptors is not a random fluctuation.

Table 12 shows the results of an analysis of neurome gene expression data (450 genes) from The Cancer Genome Atlas (TCGA), highlighting genes that were overexpressed in particular cancers present in the TCGA collection. Overexpressed gene-study pairs are selected if a gene was

overexpressed in >20% of patients in a given study (frequently overexpressed) or if the mean Z score for patients with overexpression was >10 SD above the mean (abundantly overexpressed).

TABLE 11 A: ADRB2 EXPRESSION IN CANCER

Cancer type N FKPM FKPM FKPM

<0 0-2 >2

UT-Uterine Cancer 1 1 90.9% 9.1 % 0.0%

TABLE 11 B: ADRB3 EXPRESSION IN CANCER

Cancer type N FKPM FKPM FKPM

<0 0-2 >2

ADRB3

BL-Bladder Cancer 10 100.0% 0.0% 0.0%

BN-Brain Cancer 6 100.0% 0.0% 0.0%

BR-Breast Cancer 16 100.0% 0.0% 0.0%

CR-Colorectal Cancer 47 100.0% 0.0% 0.0%

ES-Esophageal Cancer 20 100.0% 0.0% 0.0%

GS-GIST 14 78.6% 7.1 % 14.3%

HN-Head and Neck Cancer 10 80.0% 10.0% 10.0%

Kl-Kidney Cancer 7 100.0% 0.0% 0.0%

LU-Lung Cancer 194 100.0% 0.0% 0.0%

ME-Melanoma 95 100.0% 0.0% 0.0%

OV-Ovarian Cancer 19 100.0% 0.0% 0.0%

PA-Pancreatic Cancer 24 100.0% 0.0% 0.0%

SA-Sarcoma 57 84.2% 5.3% 10.5%

UT-Uterine Cancer 1 1 100.0% 0.0% 0.0%

TABLE 11 C: CHRM3 EXPRESSION IN CANCER

Cancer type N FKPM FKPM FKPM

<0 0-2 >2

CHRM3

BL-Bladder Cancer 10 70.0% 30.0% 0.0%

BN-Brain Cancer 6 16.7% 33.3% 50.0%

BR-Breast Cancer 16 62.5% 18.8% 18.8%

CR-Colorectal Cancer 47 25.5% 34.0% 40.4%

ES-Esophageal Cancer 20 75.0% 20.0% 5.0%

GS-GIST 14 50.0% 14.3% 35.7%

HN-Head and Neck Cancer 10 50.0% 40.0% 10.0%

Kl-Kidney Cancer 7 71 .4% 14.3% 14.3%

LU-Lung Cancer 194 60.8% 29.9% 9.3%

ME-Melanoma 95 69.5% 20.0% 10.5%

OV-Ovarian Cancer 19 52.6% 42.1 % 5.3%

PA-Pancreatic Cancer 24 79.2% 20.8% 0.0%

SA-Sarcoma 57 78.9% 10.5% 10.5% Cancer type N FKPM FKPM FKPM

<0 0-2 >2

UT-Uterine Cancer 1 1 54.5% 27.3% 18.2%

TABLE 11 D: DRD2 EXPRESSION IN CANCER

Cancer type N FKPM FKPM FKPM

<0 0-2 >2

DRD2

BL-Bladder Cancer 10 70.0% 0.0% 30.0%

BN-Brain Cancer 6 66.7% 16.7% 16.7%

BR-Breast Cancer 16 68.8% 31 .3% 0.0%

CR-Colorectal Cancer 47 63.8% 27.7% 8.5%

ES-Esophageal Cancer 20 95.0% 5.0% 0.0%

GS-GIST 14 100.0% 0.0% 0.0%

HN-Head and Neck Cancer 10 100.0% 0.0% 0.0%

Kl-Kidney Cancer 7 100.0% 0.0% 0.0%

LU-Lung Cancer 194 67.0% 9.3% 23.7%

ME-Melanoma 95 95.8% 3.2% 1 .1 %

OV-Ovarian Cancer 19 68.4% 21 .1 % 10.5%

PA-Pancreatic Cancer 24 100.0% 0.0% 0.0%

SA-Sarcoma 57 71 .9% 12.3% 15.8%

UT-Uterine Cancer 1 1 90.9% 9.1 % 0.0%

TABLE 12: OVEREXPRESSION OF NEUROME GENES IN CANCER

ADCY5

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

ADCY6

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Thyroid Carcinoma (TCGA, Provisional)

ADCY7

Uterine Carcinosarcoma (TCGA, Provisional)

ADK

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) ADRBK1

Glioblastoma Multiforme (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) ADRBK2

Uterine Carcinosarcoma (TCGA, Provisional)

AKAP10

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Brain Lower Grade Glioma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

AKAP1 1

Adrenocortical Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional) Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

AKAP6

Brain Lower Grade Glioma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

AKAP7

Mesothelioma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

AKAP8

Bladder Urothelial Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

ALDH5A1

Brain Lower Grade Glioma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

ALDH9A1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

ATP1 A1

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

ATP2A2

Cholangiocarcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

BACE1

Cholangiocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CASK

Uterine Carcinosarcoma (TCGA, Provisional) CDK5

Esophageal Carcinoma (TCGA, Provisional)

CDK5R1

Uterine Carcinosarcoma (TCGA, Provisional)

CHRNB1

Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

COMT

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

CRCP

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Brain Lower Grade Glioma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CSK

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CSNK1 E

Brain Lower Grade Glioma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) CYSLTR2

Uterine Carcinosarcoma (TCGA, Provisional)

DAG LA

Uterine Carcinosarcoma (TCGA, Provisional)

DAG LB

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

DDR1

Brain Lower Grade Glioma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

DPYSL2

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

EEF2K

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

ERBB2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

F2RL1

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

FNTA

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional) Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Nature 2013)

GABARAP

Colorectal Adenocarcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Nature 2013)

GNA1 1

Brain Lower Grade Glioma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

GNAI2

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Glioblastoma (TCGA, Cell 2013)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional) Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

GNAI3

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Brain Lower Grade Glioma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Head and Neck Squamous Cell Carcinoma (TCGA, Provisional) Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

GNA01

Brain Lower Grade Glioma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

GNAQ

Adrenocortical Carcinoma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Uterine Carcinosarcoma (TCGA, Provisional)

GNAS

Acute Myeloid Leukemia (TCGA, NEJM 2013) Acute Myeloid Leukemia (TCGA, Provisional)

GNB1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Brain Lower Grade Glioma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

GNB2

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

GNB4

Uterine Carcinosarcoma (TCGA, Provisional)

GNB5

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

GNG10

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional) Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

HNMT

Pancreatic Adenocarcinoma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

IL6R

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

KRAS

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

LIFR

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

LRTOMT

Adrenocortical Carcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

MAOB

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

MAP2K1

Colorectal Adenocarcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

MAP2K2

Cholangiocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

MAP3K1

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Uterine Carcinosarcoma (TCGA, Provisional)

MAPK1

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional) Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma Multiforme (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional) Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Pancreatic Adenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional) Stomach Adenocarcinoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) MAPK14

Brain Lower Grade Glioma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Lung Squamous Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Pancreatic Adenocarcinoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

MAPK3

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Kidney Renal Clear Cell Carcinoma (TCGA, Provisional) Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Uterine Carcinosarcoma (TCGA, Provisional)

NMUR1

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

NSF

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional) Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Pheochromocytoma and Paraganglioma (TCGA, Provisional) OGFR

Glioblastoma Multiforme (TCGA, Provisional)

PARK2

Adrenocortical Carcinoma (TCGA, Provisional)

Glioblastoma Multiforme (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

PARK7

Brain Lower Grade Glioma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional) Uveal Melanoma (TCGA, Provisional)

PDE4A

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Kidney Renal Clear Cell Carcinoma (TCGA, Provisional) Lung Adenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

PDE4D

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

PDPK1

Glioblastoma (TCGA, Cell 2013)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Kidney Chromophobe (TCGA, Cancer Cell 2014)

PINK1

Brain Lower Grade Glioma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

PKD2 Papillary Thyroid Carcinoma (TCGA, Cell 2014)

PLCB1

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

PLCD1

Uveal Melanoma (TCGA, Provisional)

PLCG1

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

PLCL2

Thymoma (TCGA, Provisional)

PPP1 CA

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

PPP1 R12A

Cholangiocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Skin Cutaneous Melanoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

PPP1 R9A

Brain Lower Grade Glioma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

PPP2CA

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

PPP3CA

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

PPP3CB

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Thymoma (TCGA, Provisional) Thyroid Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

PPP3CC

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

PPP3R1

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

PPT1

Brain Lower Grade Glioma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional) Uveal Melanoma (TCGA, Provisional)

PRKACA

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Provisional)

PRKAR1 A

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

PRKAR2A

Esophageal Carcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

PTEN

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Brain Lower Grade Glioma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma Multiforme (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Prostate Adenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Thymoma (TCGA, Provisional) Thyroid Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) PTGER3

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

PTK2

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Papillary Thyroid Carcinoma (TCGA, Cell 2014)

Pheochromocytoma and Paraganglioma (TCGA, Provisional) Prostate Adenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

PTK2B

Colorectal Adenocarcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Prostate Adenocarcinoma (TCGA, Provisional)

PXK

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Pheochromocytoma and Paraganglioma (TCGA, Provisional) RAB3GAP1

Brain Lower Grade Glioma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Head and Neck Squamous Cell Carcinoma (TCGA, Provisional) Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Kidney Renal Clear Cell Carcinoma (TCGA, Provisional) Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Papillary Thyroid Carcinoma (TCGA, Cell 2014) Pheochromocytoma and Paraganglioma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Sarcoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Thyroid Carcinoma (TCGA, Provisional)

RIC3

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Pheochromocytoma and Paraganglioma (TCGA, Provisional)

RNLS

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

SORCS3

Brain Lower Grade Glioma (TCGA, Provisional)

SRC

Adrenocortical Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

TRPV1

Liver Hepatocellular Carcinoma (TCGA, Provisional)

VIPR2

Thymoma (TCGA, Provisional)

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., colorectal cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a neuromodulating agent based on neurome gene expression in a biopsy. For example, a biopsy can be collected from a patient's colorectal cancer tumor, and the tumor can be analyzed for CHRM3 RNA content by qPCR or RNAseq, and analyzed for CHRM3 protein content by ELISA or Western Blot analysis. The expression of CHRM3 can be compared to the expression of a housekeeping gene, and if the tumor has a higher relative expression of CHRM3 (e.g., 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold higher relative expression of CHRM3 compared to a housekeeping gene), it will be identified as overexpressing CHRM3. A patient with a tumor that overexpresses CHRM3 is a good candidate for treatment with a CHRM3 antagonist (e.g., darifenacin, atropine, dicycloverine,

hyoscyamine, alcidium bromide, 4-DAMP, darifenacin, DAU-5884, oxybutynin, tiotropium, zamifenacin, and tolterodine). To this end, a physician of skill in the art can administer a patient with a tumor that overexpresses CHRM3 a selective CHRM3 antagonist (e.g., Darifenacin). The CHRM3 antagonist can be administered locally (e.g., injected into the CHRM3 overexpressing tumor) to decrease tumor growth or volume. The CHRM3 antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, The CHRM3 antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more).

The CHRM3 antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the CHRM3 antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the CHRM3 antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the CHRM3 antagonist has successfully treated the cancer.

Example 20 - Neurome gene under-expression in cancer

One form of cancer neuro-dependence is marked by the under-expression of neurome genes, like neurotransmitter or neuropeptide receptors, synaptic junction proteins, neuronal growth factors, structural proteins, channels, transporters, signaling proteins, or others as listed in Table 7 or Table 8. Tumors that under-express neurome genes may be suppressing their expression in order to evade mechanisms of cell growth control and hyper-proliferate. These under-expressed genes and proteins represent potential targets for therapeutic intervention, either by re-introducing the protein by a means of overexpression, such as mRNA or gene therapy, or by identifying alternate signaling paths to recover the growth-suppressive signals.

Table 13 shows the results of an analysis of neurome gene expression data (450 genes) from The Cancer Genome Atlas (TCGA), highlighting genes that were under-expressed in particular cancers present in the TCGA collection. Under-expressed gene-study pairs are selected if a gene was under- expressed in >10% of patients in a given study (frequently under-expressed) or if the mean Z score for patients with under-expression was <2.0 SD below the mean (abundantly under-expressed).

TABLE 13: UNDER-EXPRESSION OF NEUROME GENES IN CANCER

ABAT

Adrenocortical Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

ACHE

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional) ADCY1

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

ADCY10

Cholangiocarcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

ADCY2

Cholangiocarcinoma (TCGA, Provisional)

ADCY3

Uterine Carcinosarcoma (TCGA, Provisional)

ADCY4

Uterine Carcinosarcoma (TCGA, Provisional)

ADCY5

Lung Adenocarcinoma (TCGA, Nature 2014)

Uterine Carcinosarcoma (TCGA, Provisional)

ADCY8

Bladder Urothelial Carcinoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

ADCY9

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

ADCYAP1

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) ADRA1 A

Bladder Urothelial Carcinoma (TCGA, Provisional)

ADRA1 D

Uterine Carcinosarcoma (TCGA, Provisional)

ADRA2A

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

ADRB1

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

AGTR1

Uterine Carcinosarcoma (TCGA, Provisional)

AKAP1

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

AKAP10

Sarcoma (TCGA, Provisional)

AKAP1 1

Colorectal Adenocarcinoma (TCGA, Provisional)

AKAP14 Testicular Germ Cell Cancer (TCGA, Provisional)

AKAP8

Adrenocortical Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) AKAP9

Adrenocortical Carcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

ALDH5A1

Uterine Carcinosarcoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

ALDH9A1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Nature 2013) Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) ALOX15

Cholangiocarcinoma (TCGA, Provisional)

ATP1 A2

Skin Cutaneous Melanoma (TCGA, Provisional)

AVPR1 B

Uterine Carcinosarcoma (TCGA, Provisional)

BCHE

Lung Squamous Cell Carcinoma (TCGA, Provisional) CALCR

Cholangiocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional) Stomach Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CAMK2A

Adrenocortical Carcinoma (TCGA, Provisional)

CARTPT

Cholangiocarcinoma (TCGA, Provisional) Mesothelioma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

CASK

Uterine Carcinosarcoma (TCGA, Provisional)

CCKAR

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Pancreatic Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CCKBR

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

CDK5

Adrenocortical Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

CDK5R1

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CHRNB1

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CHRNB2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Thymoma (TCGA, Provisional)

CHRNB3

Adrenocortical Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

CPA4

Adrenocortical Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

CRCP

Adrenocortical Carcinoma (TCGA, Provisional)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional) Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) Mesothelioma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

CRHR1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

CRLF1

Mesothelioma (TCGA, Provisional)

CSNK1 E

Testicular Germ Cell Cancer (TCGA, Provisional)

CYSLTR2

Uterine Carcinosarcoma (TCGA, Provisional)

DAG LB

Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

DCLK1

Uterine Carcinosarcoma (TCGA, Provisional)

DDC

Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

DDR1

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

DGKI

Adrenocortical Carcinoma (TCGA, Provisional) Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

DRD2

Cholangiocarcinoma (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Skin Cutaneous Melanoma (TCGA, Provisional)

DRD3

Uterine Carcinosarcoma (TCGA, Provisional)

DRD4

Uterine Carcinosarcoma (TCGA, Provisional)

DRD5

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

EEF2K

Adrenocortical Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

ERBB2

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Nature 2013)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

FNTA

Adrenocortical Carcinoma (TCGA, Provisional)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

FRS2

Bladder Urothelial Carcinoma (TCGA, Nature 2014) Bladder Urothelial Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Sarcoma (TCGA, Provisional)

FRS3

Cholangiocarcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

FSHR

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

GABRA1

Acute Myeloid Leukemia (TCGA, NEJM 2013)

Acute Myeloid Leukemia (TCGA, Provisional)

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013)

Kidney Renal Clear Cell Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) Pancreatic Adenocarcinoma (TCGA, Provisional)

GABRA2

Adrenocortical Carcinoma (TCGA, Provisional)

GABRA3

Adrenocortical Carcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

GABRA4

Adrenocortical Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

GABRA5

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

GABRA6

Sarcoma (TCGA, Provisional)

GABRB2

Adrenocortical Carcinoma (TCGA, Provisional)

GABRD

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional) Uterine Carcinosarcoma (TCGA, Provisional)

GABRG2

Cholangiocarcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) GABRR1

Adrenocortical Carcinoma (TCGA, Provisional)

GABRR3

Uveal Melanoma (TCGA, Provisional)

GAD2

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) GAL

Lung Adenocarcinoma (TCGA, Nature 2014)

GALR3

Mesothelioma (TCGA, Provisional)

GCGR

Lung Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

GCHFR

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

GFRA3

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Uterine Carcinosarcoma (TCGA, Provisional)

GFRA4

Thymoma (TCGA, Provisional)

GHRHR

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

GIP

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Uterine Carcinosarcoma (TCGA, Provisional)

GLRA1

Adrenocortical Carcinoma (TCGA, Provisional)

GLRA4

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional) GLUL

Breast Invasive Carcinoma (TCGA, Cell 2015)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

GNA1 1

Glioblastoma Multiforme (TCGA, Provisional)

GNAI1

Adrenocortical Carcinoma (TCGA, Provisional)

GNAI3

Uterine Carcinosarcoma (TCGA, Provisional)

GNAL

Uterine Carcinosarcoma (TCGA, Provisional)

GNA01

Adrenocortical Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

GNAS

Colorectal Adenocarcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

GNB2

Esophageal Carcinoma (TCGA, Provisional)

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

GNB4

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Esophageal Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

GNG4

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

GNG5

Uterine Carcinosarcoma (TCGA, Provisional)

GNG8

Adrenocortical Carcinoma (TCGA, Provisional) GRIK5

Uterine Carcinosarcoma (TCGA, Provisional)

GRIN2A

Adrenocortical Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

GRIN2B

Uterine Carcinosarcoma (TCGA, Provisional)

GRIN2B.1

Uterine Carcinosarcoma (TCGA, Provisional)

GRIN2C

Pancreatic Adenocarcinoma (TCGA, Provisional)

GRIN2D

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

GRIN3A

Sarcoma (TCGA, Provisional)

GRM5

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

GRM7

Uveal Melanoma (TCGA, Provisional)

GRPR

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

HMOX1

Uterine Corpus Endometrial Carcinoma (TCGA, Nature 2013)

HMOX2

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

HRH3

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Breast Invasive Carcinoma (TCGA, Cell 2015)

Cholangiocarcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

HTR1 A

Adrenocortical Carcinoma (TCGA, Provisional)

HTR1 D

Kidney Chromophobe (TCGA, Cancer Cell 2014) Kidney Chromophobe (TCGA, Provisional)

HTR1 E

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

HTR1 F

Cholangiocarcinoma (TCGA, Provisional)

HTR2C

Brain Lower Grade Glioma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

HTR3C

Esophageal Carcinoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

HTR3D

Esophageal Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

HTR3E

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional) Lung Squamous Cell Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

HTR5A

Adrenocortical Carcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

HTR6

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

HTR7

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

KISS1 R

Thymoma (TCGA, Provisional)

KRAS Esophageal Carcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional) Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Stomach Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

LHCGR

Skin Cutaneous Melanoma (TCGA, Provisional)

LPAR3

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) Kidney Renal Clear Cell Carcinoma (TCGA, Provisional) LRRK2

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional) LRTOMT

Esophageal Carcinoma (TCGA, Provisional)

MAP2K2

Glioblastoma Multiforme (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

MAP3K1

Adrenocortical Carcinoma (TCGA, Provisional)

MAPK1

Lung Squamous Cell Carcinoma (TCGA, Provisional) MAPK14

Liver Hepatocellular Carcinoma (TCGA, Provisional) Skin Cutaneous Melanoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

MC1 R

Adrenocortical Carcinoma (TCGA, Provisional)

MC2R

Uterine Carcinosarcoma (TCGA, Provisional)

MC3R

Bladder Urothelial Carcinoma (TCGA, Nature 2014) Colorectal Adenocarcinoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

MC4R

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Prostate Adenocarcinoma (TCGA, Provisional)

MC5R

Cholangiocarcinoma (TCGA, Provisional) MCHR1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Prostate Adenocarcinoma (TCGA, Provisional)

MCHR2

Prostate Adenocarcinoma (TCGA, Provisional)

MME

Cholangiocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

MMP13

Cholangiocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

MRAP

Uterine Carcinosarcoma (TCGA, Provisional)

NAALAD2

Esophageal Carcinoma (TCGA, Provisional)

NAMPT

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

NGFR

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

NMUR2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional) NOS1

Adrenocortical Carcinoma (TCGA, Provisional)

Cholangiocarcinoma (TCGA, Provisional)

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

NPBWR1

Testicular Germ Cell Cancer (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) NPBWR2

Adrenocortical Carcinoma (TCGA, Provisional)

NPFFR2

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

NPSR1

Cholangiocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

NPY2R

Adrenocortical Carcinoma (TCGA, Provisional)

NPY6R

Uterine Carcinosarcoma (TCGA, Provisional)

NQ01

Testicular Germ Cell Cancer (TCGA, Provisional)

NR4A2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

NSF

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

NTRK1

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

NTRK2

Adrenocortical Carcinoma (TCGA, Provisional)

NTSR1

Mesothelioma (TCGA, Provisional)

NTSR2

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional) OGFR

Adrenocortical Carcinoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Provisional)

οχτ

Adrenocortical Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

P2RX3

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

P2RY1 Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015)

P2RY1 1

Adrenocortical Carcinoma (TCGA, Provisional)

P2RY13

Uveal Melanoma (TCGA, Provisional)

P2RY6

Cholangiocarcinoma (TCGA, Provisional)

PAH

Esophageal Carcinoma (TCGA, Provisional)

PARK7

Uterine Carcinosarcoma (TCGA, Provisional)

PCSK1

Esophageal Carcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

PCSK1 N

Esophageal Carcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

PDE4D

Cholangiocarcinoma (TCGA, Provisional)

PLCG1

Bladder Urothelial Carcinoma (TCGA, Nature 2014)

Bladder Urothelial Carcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

PLCL2

Uveal Melanoma (TCGA, Provisional)

PPP1 R12A

Adrenocortical Carcinoma (TCGA, Provisional)

Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (TCGA, Provisional)

PPP1 R1 B

Breast Invasive Carcinoma (TCGA, Cell 2015)

Breast Invasive Carcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

PPP1 R9A

Kidney Renal Papillary Cell Carcinoma (TCGA, Provisional) Head and Neck Squamous Cell Carcinoma (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Lung Squamous Cell Carcinoma (TCGA, Provisional)

Ovarian Serous Cystadenocarcinoma (TCGA, Provisional)

Pancreatic Adenocarcinoma (TCGA, Provisional)

Skin Cutaneous Melanoma (TCGA, Provisional)

Stomach Adenocarcinoma (TCGA, Nature 2014)

Stomach Adenocarcinoma (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional)

Uveal Melanoma (TCGA, Provisional)

PTPRN2

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

PXK

Kidney Renal Clear Cell Carcinoma (TCGA, Nature 2013) QRFPR

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

Mesothelioma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

RAMP3

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

RXFP1

Mesothelioma (TCGA, Provisional)

RXFP4

Glioblastoma (TCGA, Cell 2013)

Glioblastoma Multiforme (TCGA, Provisional)

Liver Hepatocellular Carcinoma (TCGA, Provisional)

Thymoma (TCGA, Provisional)

SORCS1

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

SORCS3

Head and Neck Squamous Cell Carcinoma (TCGA, Provisional) SRC

Adrenocortical Carcinoma (TCGA, Provisional)

Colorectal Adenocarcinoma (TCGA, Provisional)

Esophageal Carcinoma (TCGA, Provisional)

Head and Neck Squamous Cell Carcinoma (TCGA, Nature 2015) Ovarian Serous Cystadenocarcinoma (TCGA, Provisional) Stomach Adenocarcinoma (TCGA, Provisional)

Uterine Carcinosarcoma (TCGA, Provisional)

SSTR3

Mesothelioma (TCGA, Provisional)

SSTR4

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) SSTR5

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

SULF2

Cholangiocarcinoma (TCGA, Provisional)

TACR2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

Testicular Germ Cell Cancer (TCGA, Provisional)

TACR3

Uterine Carcinosarcoma (TCGA, Provisional)

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) TGM2

Kidney Chromophobe (TCGA, Cancer Cell 2014)

Kidney Chromophobe (TCGA, Provisional)

TPH1

Lung Adenocarcinoma (TCGA, Nature 2014)

TPH2

Sarcoma (TCGA, Provisional)

TRHR

Lung Adenocarcinoma (TCGA, Nature 2014)

Lung Adenocarcinoma (TCGA, Provisional)

TRPC4

Cholangiocarcinoma (TCGA, Provisional)

USP46

Adrenocortical Carcinoma (TCGA, Provisional)

UTS2R

Uterine Corpus Endometrial Carcinoma (TCGA, Provisional) VIPR2

Uterine Carcinosarcoma (TCGA, Provisional)

XCR1

Uveal Melanoma (TCGA, Provisional)

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., rhabdomyosarcoma), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a neuromodulating agent based on neurome gene expression in a biopsy. For example, a tissue sample can be collected from a patient's rhabdomyosarcoma, and the sample can be analyzed for acetylcholinesterase (ACHE) expression by qPCR or RNAseq. The expression of ACHE can be compared to the expression of a housekeeping gene, and if the tumor has a lower relative expression of ACHE (e.g., 1 .5, 2, 2.5, 3, 4, 5, or 10 or more fold lower relative expression of ACHE compared to a housekeeping gene), it will be identified as under-expressing ACHR. A patient with ACHE under-expression in a cancer can be treated by restoring acetylcholine signaling. To this end, a physician of skill in the art can administer a patient with a tumor that under-expresses ACHE

acetylcholine or a muscarinic or nicotinic receptor agonist (e.g., AF102B, AF267B, pilocarpine, cevimeline, bethanechol, carbachol, and methacholine). The nicotinic receptor agonist can be administered locally (e.g., injected into an ACHE under-expressing tumor) to decrease tumor growth or volume. The nicotinic receptor agonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the nicotinic receptor agonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more).

The nicotinic receptor agonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the nicotinic receptor agonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the nicotinic receptor agonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the nicotinic receptor agonist has successfully treated the cancer.

Example 21 - Neurome gene co-expression with biosynthetic pathway gene

One form of cancer neuro-dependence is the co-expression within a tumor of the genes necessary for the enzymatic biosynthesis or recycling of a neurotransmitter or the genes encoding a neuropeptide, and the genes for the cognate neurotransmitter or neuropeptide receptor. This co- expression suggests that cancer cells may produce their own neurotransmitters, and then capture/detect them in a feed-forward autocrine or paracrine loop to promote growth and proliferation in a nerve- independent fashion. Neural signaling pathways may not require nerves to be present and active.

In such a case, the biosynthetic enzymes are potential drug targets for cancers in which these autocrine loops are active - especially since these autocrine loops may result in a higher local concentration of ligand at the site, as well as enhanced expression of the cognate receptor, which may help in localizing a therapy to the proper site for activity; the biosynthetic enzymes (or the presence of enzyme & receptor) can be a "Companion diagnostic" to assess whether a patient is a good candidate for treatment. A patient with a tumor that expresses both a gene necessary for the enzymatic biosynthesis or recycling of a neurotransmitter or a gene encoding a neuropeptide, and a gene for the cognate neurotransmitter or neuropeptide receptor can be treated by blocking the receptor (e.g., with a neurotransmitter or neuropeptide antagonist), disrupting the enzyme (e.g., targeting the synthetic enzyme with an inhibitory RNA), or disrupting the neurotransmitter or neuropeptide (e.g., using an antibody to block or sequester the neurotransmitter or neuropeptide).

The tables below show the results of our analysis of gene expression data in the Cancer Cell Line Encyclopedia (CCLE) for cancer cell lines that co-express the rate-limiting enzyme for the biosynthesis of norepinephrine, acetylcholine, and serotonin, along with at least one of the receptors for these neurotransmitters and are thus candidates for therapy along this axis.

TABLE 14A: Cell lines that express tyrosine hydroxylase (TH) and any beta adrenergic receptor (ADRB)

CELL LINE CANCER TYPE NAME

SKBR3 BREAST

UACC893 BREAST

42MGBA CENTRAL NERVOUS

SYSTEM

KS1 CENTRAL NERVOUS

SYSTEM

YH13 CENTRAL NERVOUS

SYSTEM

RL952 ENDOMETRIUM

CL14 LARGE INTESTINE

CL40 LARGE INTESTINE

COLO201 LARGE INTESTINE

LS1034 LARGE INTESTINE

LS123 LARGE INTESTINE

SNU1033 LARGE INTESTINE

SNU1 197 LARGE INTESTINE

SW1417 LARGE INTESTINE

SW480 LARGE INTESTINE

SW620 LARGE INTESTINE

T84 LARGE INTESTINE

HCC1833 LUNG

NCIH1915 LUNG

NCIH2126 LUNG

NCIH2347 LUNG

NCIH292 LUNG

NCIH358 LUNG

NCIH854 LUNG

PCM LUNG

JHESOAD1 OESOPHAGUS

OVCAR8 OVARY

BXPC3 PANCREAS

DANG PANCREAS

HS766T PANCREAS

PATU8902 PANCREAS

PK59 PANCREAS

T3M4 PANCREAS

YAPC PANCREAS

PC3 PROSTATE CELL LINE CANCER TYPE

NAME

A253 SALIVARY GLAND

ECC10 STOMACH

GSS STOMACH

KATOIII STOMACH

OCUM1 STOMACH

SNU216 STOMACH

SNU719 STOMACH

CAL62 THYROID

SCC4 UPPER AERODIGESTIVE

TRACT

5637 URINARY TRACT

TABLE 14B: Cell lines that express acetylcholinesterase (ACHE) and any cholinergic receptor

(CHRM/N)

CELL LINE CANCER TYPE

NAME

T3M4 PANCREAS

TABLE 14C: Cell lines that express tryptophan hydroxylase (TPH1) and any serotonin receptor (HTR)

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., lung cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a neuromodulating agent based on neurome gene expression in a biopsy. For example, a tissue sample can be collected from a patient's lung cancer and analyzed for RNA expression by qPCR or RNAseq analysis, and the lung cancer can be found to express both tryptophan hydroxylase and serotonin receptor HTR2A. This neurome gene expression suggests that the patient's tumor may have co-opted an autocrine serotonin signaling loop to drive growth. To reduce the autocrine signaling, a physician of skill in the art can administer a serotonin blocking antibody, an inhibitory RNA that targets tryptophan hydroxylate, or an HTR2A antagonist (e.g., trazodone, mirtazapine, nefazodone, pizotifen, and hydroxyzine). The HTR2A antagonist can be administered locally (e.g., injected into the lung cancer) to decrease tumor growth or volume. The HTR2A antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the HTR2A antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more).

The HTR2A antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%,

30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the HTR2A antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the HTR2A antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the HTR2A antagonist has successfully treated the cancer.

Example 22 - Neurotrophic factor overexpression in cancer

One form of cancer neuro-dependence is the expression by the cancer cells of neurotrophic factors that promote the growth of neurons into the tumor and the surrounding microenvironment. These neurons may then provide growth-promoting signals to the tumor. As such, inhibition of neurotrophic factors in tumors that express them may prevent the ingrowth of neurons and thus induce a growth- inhibitory effect on the tumor.

Tables 15A and 15B below show gene expression assessed by RNAseq for two common neurotrophic factors NGF and BDNF (a complete list of neurotrophic factors is provided in Table 7). Each table displays RNAseq data for a particular neurotrophic factor in tumor samples from patients with different types of cancer. Gene expression assessed using RNAseq was scored by log2(FPKM). Values >0 are deemed to be "overexpressed" in this assay. The table shows the percentage of the total number of tumors analyzed from each cancer type (N) that overexpress the neurotrophic factor.

TABLE 15A: NGF EXPRESSION IN CANCER

Cancer type N FKPM FKPM FKPM

<0 0-2 >2

ME-Melanoma 135 95.6% 2.2% 2.2%

OV-Ovarian Cancer 41 92.7% 2.4% 4.9%

PA-Pancreatic Cancer 108 97.2% 1 .9% 0.9%

SA-Sarcoma 71 49.3% 29.6% 21 .1 %

UT-Uterine Cancer 1 1 100.0% 0.0% 0.0%

TABLE 15B: BDNF EXPRESSION IN CANCER

Example 23 - Chrna6 correlates with 5 year survival in cancer patients We evaluated the expression of nicotinic receptor Chrna6 in the TCGA GSE41721 (non-small cell lung cancer) and GSE1 7536 (colorectal cancer) data sets to determine whether there was a correlation between Chrna6 expression level and survival. We analyzed data from 275 non-small cell lung cancer (NSCLC) patients and 177 colorectal cancer (CRC) patients. Expression was normalized to CD3G in order to account for differential immune infiltration. We observed a significant improvement in 5 year survival in both NSCLC and CRC patients whose cancer expressed low levels of Chrna6 compared to NSCLC and CRC patients whose cancer expressed high levels of Chrna6 (FIGS. 9A-9B). These data suggest that high levels of Chrna6 lead to worse outcomes for patients with cancer. Example 24 - Treatment of a patient with NSLC with a Chrna6 antagonist

According to the methods disclosed herein, a physician of skill in the art can treat a patient, such as a human patient with cancer (e.g., non-small cell lung cancer), so as to inhibit cancer growth, reduce tumor burden, or slow disease progression. The method of treatment can include diagnosing or identifying a patient as a candidate for treatment with a neuromodulating agent based on neurome gene expression in a biopsy. For example, a tissue sample can be collected from a patient's non-small cell lung cancer and analyzed for RNA expression by qPCR or RNAseq analysis, and the lung cancer can be found to express high levels of Chrna6. To treat the patient, a physician of skill in the art can administer a neuromodulating agent that decreases Chrna6 expression or function (e.g., an siRNA directed to Chrna6 or a Chrna6 antagonist, e.g., mecamylamine). The Chrna6 antagonist can be administered locally (e.g., injected into the non-small cell lung cancer or formulated for inhalation) to decrease tumor growth or volume. The Chrna6 antagonist is administered in a therapeutically effective amount, such as from 10 μg/kg to 500 mg/kg (e.g., 10 μg/kg, 100 μg/kg, 500 μg/kg, 1 mg/kg, 10 mg/kg, 50 mg/kg, 100 mg/kg, 250 mg/kg, or 500 mg/kg). In some embodiments, the Chrna6 antagonist is administered bimonthly, once a month, once every two weeks, or at least once a week or more (e.g., 1 , 2, 3, 4, 5, 6, or 7 times a week or more).

The Chrna6 antagonist is administered to the patient in an amount sufficient to decrease tumor growth decrease tumor burden, or increase progression free survival by 10% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). Tumor growth and tumor burden can be assessed using standard imaging methods (e.g., digital radiography, positron emission tomography (PET) scan, computed tomography (CT) scan, or magnetic resonance imaging (MRI) scan). Images from before and after administration of the Chrna6 antagonist can be compared to evaluate the efficacy of the treatment, and the rate of disease progression can be assessed by comparison to the patient's medical history prior to administration of the Chrna6 antagonist. A finding of a reduction in the total number of tumors, number of primary tumors, volume of tumors, growth of tumors, or rate of disease progression indicates that the Chrna6 antagonist has successfully treated the cancer.

Other Embodiments

Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

Other embodiments are in the claims.