METHODS AND COMPOSITIONS FOR TREATING NEUROENDOCRINE

PROSTATE CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/810,296 filed on February 25, 2019. Priority is claimed pursuant to 35 U.S.C. § 119. The above noted patent application is incorporated by reference as if set forth fully herein.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grants CA192642, CA218254, and CA211794 from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and grant DK108743 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] Acquired resistance to cancer treatment is a major setback to current therapies. In prostate cancer (PCa), this resistance is increasingly seen as a phenotypic transdifferentiation to a deadly form of cancer, known as small cell/neuroendocrine prostate cancer (NEPC), for which there are no effective therapies available.

SUMMARY OF THE INVENTION

[0004] Described herein are methods and compositions for treating or preventing the onset of subsets of diseases based on the expression levels of particular biomarkers.

[0005] One aspect described herein comprises a method of treating a subtype of a disease or condition in a subject by administering to the subject a therapeutically effective amount of an androgen receptor (AR)-targeting therapy and an inhibitor selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0006] In some embodiments, the method is performed, provided low levels of expression of PKCl/i are detected in a biological sample obtained from the subject, as compared to levels of expression of PKCl/i in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low levels of expression of PKCl/i are detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of expression of PKCl/i comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0007] In some embodiments, the method is performed, provided a high level of expression of an ATF4 biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the ATF4 biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the ATF4 biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the ATF4 biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0008] In some embodiments, the method is performed, provided a high level of expression of a PHGDH biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the PHGDH biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the PHGDH biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the PHGDH biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0009] In some embodiments, the method is performed, provided the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 as a biomarker detected in a biological sample obtained from the subject, as compared to a level of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. [0010] In some embodiments, the method is performed, provided low levels of expression of an androgen-receptor target are detected in a biological sample obtained from the subject, as compared to levels of expression of androgen-receptor target in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low level of the androgen-receptor target is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the low level of expression of the androgen-receptor target comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the androgen-receptor target is expressed by KLK3 (PSA).

[0011] In some embodiments, the method is performed, provided low levels of expression of neuroendocrine prostate cancer (NEPC) repressor are detected in a biological sample obtained from the subject, as compared to levels of expression of NEPC repressor in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low level of the NEPC repressor is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the low level of expression of the NEPC repressor comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC repressor is REST.

[0012] In some embodiments, the method is performed, provided a high level of expression of a NEPC biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the NEPC biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the NEPC biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the NEPC biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC biomarker is selected from the list consisting of SYP, EN02 , NCAM1, and CHGA. In some embodiments, the method is performed, wherein the expression of PKCl/i that is detected in the biological sample obtained from the subject is indicative of an increase in expression of the NEPC biomarker in the biological sample, as compared to an individual who does not have the subtype of the disease or condition.

[0013] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0014] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antagonist of DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an anti- DNA methyltransferase antibody. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises decitabine (Aza). In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises cycloleucine (Cyclo).

[0015] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an inhibitor of serine and one-carbon (SGOC) enzyme activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antagonist of SGOC enzyme. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an anti- SGOC enzyme antibody.

[0016] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase activity or expression comprises an inhibitor of S-Adenosyl methionine (SAM) activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antagonist of SAM. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an anti- SAM antibody.

[0017] In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antagonist of PHGDH. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an anti- PHGDH antibody.

[0018] In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antagonist of ATF4. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an anti- ATF4 antibody.

[0019] In some embodiments, the method is performed, wherein the inhibitor of

mTORCl activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an antagonist of mTORCl. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an anti- mTORCl antibody. [0020] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase is selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of PHGDH, an inhibitor of SGOC enzyme, and an inhibitor of SAM activity.

[0021] In some embodiments, the method is performed, wherein the inhibitor is a combination of inhibitors selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0022] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone.

[0023] In some embodiments, the method is performed, wherein the biological sample comprises blood, blood plasma, sera, or tissue biopsy. In some embodiments, the methods described herein are performed on a subject, wherein the subject is a human. In some embodiments, the methods described herein are performed on a subject, wherein the subject is a mammal.

[0024] Another aspect described herein comprises a method of preventing or reversing the onset of a subset of a disease or condition in a subject suffering from a disease or condition, comprising administering to the subject a therapeutically effective amount of an androgen receptor (AR)- targeting therapy and an inhibitor selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0025] In some embodiments, the method is performed, provided low levels of expression of PKCl/i are detected in a biological sample obtained from the subject, as compared to levels of expression of PKCl/i in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low levels of expression of PKCl/i are detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of expression of PKCl/i comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. [0026] In some embodiments, the method is performed, provided a high level of expression of an ATF4 biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the ATF4 biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the ATF4 biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the ATF4 biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0027] In some embodiments, the method is performed, provided a high level of expression of a PHGDH biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the PHGDH biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the PHGDH biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the PHGDH biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0028] In some embodiments, the method is performed, provided the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 as a biomarker detected in a biological sample obtained from the subject, as compared to a level of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0029] In some embodiments, the method is performed, provided low levels of expression of an androgen-receptor target are detected in a biological sample obtained from the subject, as compared to levels of expression of androgen-receptor target in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low level of the androgen-receptor target is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the low level of expression of the androgen-receptor target comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the androgen-receptor target is expressed by KLK3 (PSA).

[0030] In some embodiments, the method is performed, provided low levels of expression of neuroendocrine prostate cancer (NEPC) repressor are detected in a biological sample obtained from the subject, as compared to levels of expression of NEPC repressor in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the low level of the NEPC repressor is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the low level of expression of the NEPC repressor comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC repressor is REST.

[0031] In some embodiments, the method is performed, provided a high level of expression of a NEPC biomarker is detected in a biological sample obtained from the subject, as compared to a level of expression of the NEPC biomarker in an individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the high level of the NEPC biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the NEPC biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC biomarker is selected from the list consisting of SYP, EN02 , NCAM1 , and CHGA. In some embodiments, the method is performed, wherein the expression of PKCl/i that is detected in the biological sample obtained from the subject is indicative of an increase in expression of the NEPC biomarker in the biological sample, as compared to an individual who does not have the subtype of the disease or condition.

[0032] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0033] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antagonist of DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an anti- DNA methyltransferase antibody. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises decitabine (Aza). In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises cycloleucine (Cyclo).

[0034] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an inhibitor of serine and one-carbon (SGOC) enzyme activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antagonist of SGOC enzyme. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an anti- SGOC enzyme antibody. [0035] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase activity or expression comprises an inhibitor of S-Adenosyl methionine (SAM) activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antagonist of SAM. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an anti- SAM antibody.

[0036] In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antagonist of PHGDH. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an anti- PHGDH antibody.

[0037] In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antagonist of ATF4. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an anti- ATF4 antibody.

[0038] In some embodiments, the method is performed, wherein the inhibitor of

mTORCl activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an antagonist of mTORCl. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an anti- mTORCl antibody.

[0039] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase is selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of PHGDH, an inhibitor of SGOC enzyme, and an inhibitor of SAM activity. [0040] In some embodiments, the method is performed, wherein the inhibitor is a combination of inhibitors selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0041] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone.

[0042] In some embodiments, the method is performed, wherein the biological sample comprises blood, blood plasma, sera, or tissue biopsy.

[0043] In some embodiments, the methods described herein are performed on a subject, wherein the subject is a human. In some embodiments, the methods described herein are performed on a subject, wherein the subject is a mammal.

[0044] Another aspect described herein comprises a method of diagnosing a subtype of a disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of PKCl/i ; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of PKCl/i detected in the biological sample obtained from the subject are low, as compared to levels of expression of PKCl/i in an individual that does not have the subset of the disease or condition.

[0045] In some embodiments, the method is performed, wherein the low levels of expression of PKCl/i are detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of expression of PKCl/i comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0046] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0047] Another aspect described herein comprises a method of diagnosing a subtype of a disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of ATF4; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of ATF4 detected in the biological sample obtained from the subject are high, as compared to levels of expression of ATF4 in an individual that does not have the subset of the disease or condition.

[0048] In some embodiments, the method is performed, wherein the high levels of expression of ATF4 are detected by an assay comprising polymerase chain reaction (PCR), reverse

transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of expression of ATF4 comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0049] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma. [0050] Another aspect described herein comprises a method of diagnosing a subtype of a disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of PHGDH; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of PHGDH detected in the biological sample obtained from the subject are high, as compared to levels of expression of PHGDH in an individual that does not have the subset of the disease or condition.

[0051] In some embodiments, the method is performed, wherein the high levels of expression of PHGDH are detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of expression of PHGDH comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0052] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0053] Another aspect described herein comprises a method of diagnosing a subtype of a disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1; and diagnosing the subject with the subset of the disease or condition, provided the levels of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 detected in the biological sample obtained from the subject are high, as compared to levels of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 in an individual that does not have the subset of the disease or condition. [0054] In some embodiments, the method is performed, wherein the high levels of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 are detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR),

deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the levels of the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 comprise ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein.

[0055] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0056] Another aspect described herein comprises a method of diagnosing a subtype of disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of an androgen-receptor target; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of the androgen-receptor target detected in the biological sample obtained from the subject are low, as compared to levels of expression of the androgen-receptor target in an individual that does not have the subset of the disease or condition.

[0057] In some embodiments, the method is performed, wherein the low level of the androgen- receptor target is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the androgen-receptor target comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the androgen-receptor target is KLK3 (PSA).

[0058] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0059] Another aspect described herein comprises a method of diagnosing a subtype of disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of an NEPC repressor; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of the NEPC repressor detected in the biological sample obtained from the subject are low, as compared to levels of expression of the NEPC repressor in an individual that does not have the subset of the disease or condition.

[0060] In some embodiments, the method is performed, wherein the low level of the NEPC repressor is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the low level of expression of the NEPC repressor comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC repressor is REST.

[0061] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0062] Another aspect described herein comprises a method of diagnosing a subtype of disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of an NEPC biomarker; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of the NEPC biomarker detected in the biological sample obtained from the subject are high, as compared to levels of expression of the NEPC biomarker in an individual that does not have the subset of the disease or condition.

[0063] In some embodiments, the method is performed, wherein the high level of the NEPC biomarker is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of the NEPC biomarker comprises ribonucleic acid (RNA), deoxyribonucleic acid (DNA), or protein. In some embodiments, the method is performed, wherein the NEPC biomarker is selected from the list consisting of SYP, EN02 , NCAM1 , and CHGA. In some embodiments, the method is performed, wherein the expression of RKϋl/i that is detected in the biological sample obtained from the subject is indicative of an increase in expression of the NEPC biomarker in the biological sample, as compared to an individual who does not have the subtype of the disease or condition.

[0064] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in the NEPC biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0065] Another aspect described herein comprises a model of NEPC comprising a transgenic animal with a transgene comprising a mutation of LAMTOR2 S30 site to alanine and genetic deletion of PTEN in the prostate epithelia. In some embodiments, the transgenic animal overexpresses NEPC biomarkers. In some embodiments, the transgenic animal overexpresses NEPC biomarkers in stroma of tumors of the transgenic animal.

[0066] Another aspect described herein comprises a model of NEPC comprising a transgenic animal with a transgene comprising a genetic modification that eliminates expression of PTEN and PKCl/i in the prostate epithelia. In some embodiments, the transgenic animal overexpresses NEPC biomarkers. In some embodiments, the transgenic animal overexpresses NEPC biomarkers in stroma of tumors of the transgenic animal. In some embodiments, the transgenic animal comprises a mammal. In some embodiments, the transgenic animal comprises a mouse. In some embodiments, the transgenic animal comprises a rat. In some embodiments, the transgenic animal comprises a monkey. In some embodiments, the quantity of cells comprises an organoid.

[0067] In some embodiments, the transgenic animal is produced by introducing, into an organism chosen from the group consisting of an animal cell and an animal embryo, an agent that specifically binds to a chromosomal target site of the cell and causes a double-stranded DNA break to induce a mutation of LAMTOR2 S30 site to alanine, with the agent being chosen from the group consisting of a TALEN, a zinc finger nuclease, Cas9/CRISPR and a recombinase fusion protein.

[0068] In some embodiments, the transgenic animal is produced by introducing, into an organism chosen from the group consisting of an animal cell and an animal embryo, an agent that specifically binds to a chromosomal target site of the cell and causes a double-stranded DNA break to eliminate expression of PTEN and PKCl/i, with the agent being chosen from the group consisting of a TALEN, a zinc finger nuclease, Cas9/CRISPR and a recombinase fusion protein.

[0069] Another aspect described herein comprises a composition comprising a therapeutically effective amount of an androgen receptor (AR)-targeting therapy and an inhibitor selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0070] In some embodiments, the inhibitor of DNA methyltransferase activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the inhibitor of DNA methyltransferase activity or expression comprises a small molecule. In some embodiments, the inhibitor of DNA methyltransferase activity or expression comprises an antagonist of DNA methyltransf erase. In some embodiments the inhibitor of DNA methyltransf erase activity or expression comprises an anti- DNA methyltransferase antibody. In some embodiments the inhibitor of DNA methyltransferase activity or expression comprises decitabine (Aza). In some embodiments the inhibitor of DNA methyltransferase activity or expression comprises cycloleucine (Cyclo).

[0071] In some embodiments the inhibitor of DNA methyltransferase activity or expression comprises an inhibitor of serine and one-carbon (SGOC) enzyme activity or expression. In some embodiments the inhibitor of SGOC enzyme activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments the inhibitor of SGOC enzyme activity or expression comprises a small molecule. In some embodiments the inhibitor of SGOC enzyme activity or expression comprises an antagonist of SGOC enzyme. In some embodiments the inhibitor of SGOC enzyme activity or expression comprises an anti- SGOC enzyme antibody.

[0072] In some embodiments the inhibitor of DNA methyltransferase activity or expression comprises an inhibitor of S-Adenosyl methionine (SAM) activity or expression. In some embodiments the inhibitor of SAM activity or expression comprises an antibody, or antigen binding fragment. In some embodiments the inhibitor of SAM activity or expression comprises a small molecule. In some embodiments the inhibitor of SAM activity or expression comprises an antagonist of SAM. In some embodiments the inhibitor of SAM activity or expression comprises an anti- SAM antibody.

[0073] In some embodiments the inhibitor of PHGDH activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments the inhibitor of PHGDH activity or expression comprises a small molecule. In some embodiments the inhibitor of PHGDH activity or expression comprises an antagonist of PHGDH. In some embodiments the inhibitor of

PHGDH activity or expression comprises an anti- PHGDH antibody.

[0074] In some embodiments the inhibitor of ATF4 activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments the inhibitor of ATF4 activity or expression comprises a small molecule. In some embodiments the inhibitor of ATF4 activity or expression comprises an antagonist of ATF4. In some embodiments the inhibitor of ATF4 activity or expression comprises an anti- ATF4 antibody.

[0075] In some embodiments the inhibitor of mTORCl activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments the inhibitor of mTORCl activity or expression comprises a small molecule. In some embodiments the inhibitor of mTORCl activity or expression comprises an antagonist of mTORCl. In some embodiments the inhibitor of mTORCl activity or expression comprises an anti- mTORCl antibody. [0076] In some embodiments the inhibitor of DNA methyltransferase is selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of PHGDH, an inhibitor of SGOC enzyme, and an inhibitor of SAM activity.

[0077] In some embodiments the inhibitor is a combination of inhibitors selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

[0078] In some embodiments the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments the AR-targeting therapy comprises a small molecule. In some embodiments the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments the AR-targeting therapy comprises enzalutamide. In some embodiments the AR-targeting therapy comprises

abiraterone. Another aspect described herein comprises a method of diagnosing a subtype of a disease or condition in a subject in need thereof, the method comprising: obtaining a biological sample from a subject in need thereof; subjecting the biological sample to an assay suitable to detect levels of expression of hyaluronan or CD44; and diagnosing the subject with the subset of the disease or condition, provided the levels of expression of hyaluronan or CD44 detected in the biological sample obtained from the subject are high, as compared to levels of expression of hyaluronan or CD44 in an individual that does not have the subset of the disease or condition.

[0079] Another aspect described herein comprises a method of treating, preventing, or reversing the onset of a subtype of a disease or condition by administering to the subject a therapeutically effective amount of an androgen receptor (AR)-targeting therapy and an inhibitor selected from the group comprising an inhibitor of hyaluronan, an inhibitor of hyaluronan synthase, and an inhibitor of CD44.

[0080] In some embodiments, the method is performed, wherein the hyaluronan synthase is encoded by HAS1, HAS2 , or HAS 3 gene. In some embodiments, the method is performed, provided a high level of expression of hyaluronan, CD44, or a combination thereof is detected in a biological sample obtained from the subject, as compared to a level of expression of hyaluronan, CD44, or a combination thereof in an individual who does not have the disease or condition. In some embodiments, the method is performed, wherein the high level of expression of hyaluronan, CD44, or a combination thereof is detected by an assay comprising polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, genotyping array, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), single-molecule array (Simoa), or a combination thereof. In some embodiments, the method is performed, wherein the high level of expression of hyaluronan, CD44, or a combination thereof comprises ribonucleic acid (RNA),

deoxyribonucleic acid (DNA), protein, or polysaccharide.

[0081] In some embodiments, the method is performed, wherein the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by an increase in a neuroendocrine prostate cancer (NEPC) biomarker in the biological sample obtained from the subject, as compared to the individual who does not have the subtype of the disease or condition. In some embodiments, the method is performed, wherein the NEPC biomarker is selected from the list consisting of SYP, EN02 , NCAM1 , CHGA , and combinations thereof. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by acinar adenocarcinoma. In some embodiments, the method is performed, wherein the subtype of the disease or condition comprises a disease or condition characterized by ductal adenocarcinoma.

[0082] In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antibody, or antigen binding fragment. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a peptide. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antagonist of HAS1, HAS2, HAS3, or CD44. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an anti -HAS 1, anti- HAS2, anti-HAS3, or anti-CD44 antibody. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises HASl siRNA, HAS2 siRNA, HAS3 siRNA, or CD44 siRNA.

[0083] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises KLK3 siRNA. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone.

[0084] In some embodiments, the method is performed, wherein the biological sample comprises blood, blood plasma, sera, or tissue biopsy. In some embodiments, the method is performed, wherein the subject is a human. In some embodiments, the method is performed, wherein the subject is a mammal.

[0085] Another aspect described herein comprises a composition comprising a therapeutically effective amount of an androgen receptor (AR)-targeting therapy and an inhibitor selected from the group comprising an inhibitor of hyaluronan, an inhibitor of hyaluronan synthase, and an inhibitor of CD44.

BRIEF DESCRIPTION OF THE DRAWINGS

[0086] The patent application contains at least one drawing executed in color. Copies of this patent or patent application with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0087] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0088] Figure 1A shows PRKCI mRNA levels in PCa datasets separated by Normal vs. Cancer (upper graph) and Metastasis vs. Primary cancer (lower graph).

[0089] Figure IB shows the Odds Ratio of the overlap between the concepts“ PRKCI correlated” and“ PRKCI anti correlated”, and clinical subgroups generated from the specified PCa datasets.

[0090] Figure 1C shows recurrence free survival (RFS) of patients stratified by PRKCI mRNA expression (GSE21034).

[0091] Figure ID shows PRKCI mRNA levels in Adenocarcinoma and NEPC samples.

[0092] Figure IE shows PRKCI mRNA levels in GSE21034 samples classified. Adeno:

Adenocarcinoma; MET: metastasis.

[0093] Figure IF shows GSEA of NEPC signatures in PRKCI correlated genes in GSE21034.

[0094] Figure 1G shows Pearson correlation analysis of PRKCI and NEPC markers in

GSE21034. [0095] Figure 1H shows Representative staining of PKCl/i and NCAM1, quantification

(normalized values), and H&E, in a PCa cohort containing Adenocarcinoma (n = 7) and NEPC (n = 14).

[0096] Figure II shows Western blot of PKCl/i and Actin in the indicated cell lines (n = 3).

[0097] Figure 1 J shows FACS analysis of CD44 or NCAM1 in LNCaP or LNCaP-ER cells (n = 3)·

[0098] Figure IK qPCR analysis of indicated genes in sorted CD44 ^high or NCAMl ¹ ^ ¹¹ cells and western blot of NCAM1 and PKCl/i in LNCaP or LNCaP-ER cells (n = 2).

[0099] Figure 1L shows Staining of PKCl/i and NCAMl and quantification (normalized values) in an Adenocarcinoma with NEPC differentiation sample. Scale bars, 100 pm.

[0100] Figure 1M shows Gene expression levels of PRKCI, NCAM1 and KLK3 in GSE70380.

[0101] Figure 2A shows overall survival of PTEN KO (n = 9) and DKO mice (n = 12).

[0102] Figure 2B shows photographs of PTEN KO and DKO genitourinary organs.

[0103] Figure 2C shows Frequency of prostatic lesions and representative H&E of PTEN KO (n = 8) and DKO (n = 9) prostates.

[0104] Figure 2D shows Masson’s Tri chrome staining of PTEN KO (n = 5) and DKO prostates (n = 7).

[0105] Figure 2E shows Ki67 and TP63 IHC of PTEN KO (n = 5) and DKO (n = 5) prostates.

[0106] Figure 2F shows quantification of Ki67 and TP63 IHC from Figure 2E

[0107] Figure 2G shows Representative H&E of DKO prostate. Yellow line, prostatic urothelial carcinoma.

[0108] Figure 2H shows CK5, CK8 and AR IHC of PTEN KO and DKO (n = 4) prostates.

[0109] Figure 21 shows CK5, CHGA, TP63, AR and Ki67 IHC of DKO prostate with magnification of prostatic urothelial carcinoma.

[0110] Figure 2J shows FACS analysis of NCAM1 of PTEN KO and DKO (n = 3) prostate basal cells.

[0111] Figure 2K shows organoid growth of PTENKO and DKO prostate-derived organoids.

[0112] Figure 2L shows qPCR of indicated genes in PTEN KO and DKO-derived prostate organoids (n = 3-5).

[0113] Figure 2M shows average organoid size of prostate cancer-derived organoids from PTEN KO and DKO mice treated with Enzalutamide (10 mM) for 4 days (n = 3).

[0114] Figure 3A shows Western blot of indicated proteins in shNT and shPKCl/i LNCaP cells (n = 3).

[0115] Figure 3B shows qPCR of indicated genes in shNT and shPKCl/i LNCaP cells (n = 3-4). [0116] Figure 3C shows Western blot of indicated proteins in sgC, sgPKCl/i and sgPKCl/i-R C42B cells (n = 3).

[0117] Figure 3D shows qPCR of indicated genes in sgC, sgPKCl/i and sgPKCl/i-R (n=3).

[0118] Figure 3E shows GSEA of NEPC signatures in microarray data of shNT and shPKCl/i PrEC cells.

[0119] Figure 3F shows cell proliferation of shNT and shPKCl/i LNCaP cells under androgen deprivation (ADT) with or without Enzalutamide (10 mM). Western blot of PKCl/i (n = 3).

[0120] Figure 3G shows qPCR of indicated genes in shNT and shPKCl/i LNCaP cells (n = 3-6).

[0121] Figure 3H shows cell proliferation of FLAG or FLAG- PKCl/i PC3 cells in ADT and western blot (n = 3).

[0122] Figure 31 shows cell proliferation of sgC and sgPKCl/i C42B cells in ADT (n = 3).

[0123] Figure 3J shows qPCR analysis of E2F1 mRNA levels in sgC and sgPKCl/i (n = 4).

[0124] Figure 3K shows Tumor growth of xenografts of sgC, sgPKCl/i and sgPKOA-R (n = 12).

[0125] Figure 4A shows the Top 5 GSEA results of shPKCl/i vs shNT comparison of PrEC cells using compilation H.

[0126] Figure 4B shows the Top 5 GSEA results of sgPKCl/i vs sgC and sgPKCl/i vs sgPKCl/i-R comparisons of C42B cells using compilation H.

[0127] Figure 4C shows Western blot of indicated proteins in sgC, sgPKCl/i, sgPKCl/i -R WT and sgPKCl/i-R KiD (n=3).

[0128] Figure 4D shows pS6 (Ser 235/236) IF of PTEN KO and DKO prostates (n = 4).

[0129] Figure 4E shows quantification of pS6 in Figure 4D.

[0130] Figure 4F shows Western Blot of indicated proteins in sgC and sgPKCl/i treated with 50 nM rapamycin (n = 2).

[0131] Figure 4G shows qPCR of indicated genes in sgC and sgPKCl/i treated with 50 nM rapamycin (n = 5).

[0132] Figure 4H shows GSEA of“mTORCI Signaling” and“NEPC UP” genesets in the comparison of Torinl -treated LNCaP vs vehicle, GSE93603.

[0133] Figure 41 shows Volcano plot of biotinylated proteins in PKCl/i-BioID2 vs Empty- BioID2 LNCaP cells (n = 5).

[0134] Figure 4J shows double staining of RKPl/i and LAMTOR2 in LNCaP cells.

[0135] Figure 4K shows CoIP of PKCl/i and LAMTOR2 in 293FT cells transfected with FLAG-LAMTOR2 (n = 2). [0136] Figure 4L shows in vitro phosphorylation of recombinant LAMTOR2 by recombinant PKCl/i with ATPyS followed by PNBM alkylation and immunoblotting for the indicated proteins (n = 2).

[0137] Figure 4M shows in vitro phosphorylation of FL AG-tagged LAMTOR2 WT and LAMTOR2 S30A immunoprecipitates by recombinant PKCl/i with ATPyS followed by PNBM alkylation and immunoblotting for the indicated proteins (n = 3).

[0138] Figure 4N shows Western Blot of indicated proteins in C42B cells transfected with FL AG-L AMT OR2 WT or FL AG-L AMT OR2 S30A (n = 3).

[0139] Figure 40 shows immunostaining for the indicated proteins and radial distribution profiling of mean intensities from the nucleus center (n = 6 cells, each condition) in sgC and sgPKCl/i.

[0140] Figure 4P shows Western Blot of indicated proteins in sgC and sg PKCl/i treated with Ciliobrevin D (40 mM) for 8 hr (n = 2).

[0141] Figure 4Q shows LAMP2 staining and radial distribution profiling of mean intensities from the nucleus center (n= 6 cells, each condition) in LNCaP cells transfected with LAMTOR2 WT or LAMTOR2 S30A.

[0142] Figure 4R shows CoIP of mTOR and LAMTOR2 in sgC and sg PKCl/i cells transfected with FLAG-LAMTOR2 (n = 2).

[0143] Figure 4S shows CoIP of mTOR and LAMTOR2 in 293FT cells transfected with FLAG- LAMTOR2 WT or S30A (n = 2).

[0144] Figure 4T shows the model: the loss of PKCl/i promotes the perinuclear aggregate of lysosomes, which favors the interaction of mTOR with its co-activator Rheb.

[0145] Figure 5A shows upstream regulator analysis of PKCl/i-dependent genes in C42B cells

[0146] Figure 5B shows Western blot analysis of indicated proteins in sgC and sgPKCl/i treated with 50 nM rapamycin (n = 2).

[0147] Figure 5C shows ATF4 staining in PTEN KO and DKO prostates (n = 5-7) and quantification of nuclear ATF4.

[0148] Figure 5D shows Western blot analysis of indicated proteins in sgPKCl/i and sgC stably transfected with shNT or shATF4 (n = 3).

[0149] Figure 5E shows qPCR of indicated genes in sgPKCl/i and sgC stably transfected with shNT or shATF4 (n =3).

[0150] Figure 5F shows Cell proliferation of sgPKCl/i and sgC stably transfected with shNT or shATF4 (n = 3). [0151] Figure 5G shows GSEA of the geneset“SGOCP” in the comparisons sgPKCl/i vs sgC (left) and sgPKCl/i-R vs sgPKCl/i (right) and heatmap of PHGDH , PSAT1 and MΊΉI ^, Ί)2 expression with Log2FC values for the sgPKCl/i vs sgC comparison.

[0152] Figure 5H shows Western blot of indicated proteins in sgC, sgPKCl/i, sgPKCl/i-R WT and sgPKCl/i-R KiD (n= 3).

[0153] Figure 51 shows qPCR of indicated genes in sgC and sgPKCl/i stably transfected with shNT or shATF4 (n =3).

[0154] Figure 5J shows qPCR of indicated genes in sgC and sgPKCl/i treated with 50 nM rapamycin (n = 3).

[0155] Figure 5K shows Western blot analysis of indicated proteins in control and ATF4- transfected LNCaP cells (n =3).

[0156] Figure 5L shows qPCR of indicated genes in control and ATF4-transfected LNCaP cells (n= 3).

[0157] Figure 5M shows Western blot analysis of indicated proteins in sgPKCl/i and sgC stably transfected with shNT or shPHGDH (n = 3).

[0158] Figure 5N shows qPCR of indicated genes in sgC and sgPKCl/i stably transfected with shNT or shPHGDH (n= 3).

[0159] Figure 50 shows cell proliferation of sgC and sgPKCl/i stably transfected with shNT or shPHGDH (n = 3).

[0160] Figure 5P shows Fraction of labeled [U-13C6] Glucose-derived intracellular serine and glycine (n = 3). Statistical significance for sgC vs sgPKCl/i comparison.

[0161] Figure 5Q shows Isotopologue distribution of [U-13C6]Glucose-derived intracellular serine and glycine (n = 3).

[0162] Figure 5R shows Fraction of labeled [a- ¹⁵ N] Glutamine-derived intracellular glutamate (Glu), serine and glycine at 24 hr (n = 3).

[0163] Figure 6A shows GSEA of“mTORCl Signaling” Hallmark gene set in NEPC vs Adeno (Adenocarcinoma PCa) in two human sample PCa datasets.

[0164] Figure 6B shows expression values of PRKCI, ATF4 , ASNS and PHGDH in GSE64143.

[0165] Figure 6C shows expression values of the indicated genes in GSE70380.

[0166] Figure 6D shows a heatmap of PRKCI , NE markers and SGOCP genes in patient derived prostate cancer organoid lines.

[0167] Figure 6E shows mRNA expression for the indicated genes in Adeno and NEPC samples. [0168] Figure 6F shows IHC staining of p4EBPl (Thr37/46) and H&E, with quantification (normalized values) in Adenocarcinoma (n = 6) and NEPC (n = 10).

[0169] Figure 6G shows p4EBPl (Thr37/46) and PHGDH IHC, and H&E staining, in a primary NEPC lesion with adenocarcinoma (yellow-dashed line) and an adjacent NEPC lesion (black- dashed line) with quantification of PHGDH staining (normalized values) in Adenocarcinoma (n = 6) and NEPC (n =7).

[0170] Figure 6H shows double staining of SYP and ATF4 with quantification of nuclear ATF4 in Adenocarcinoma (n= 6) and NEPC (n = 13).

[0171] Figure 7A shows Dot-blot analysis of total genomic DNA methylation levels of sgC shNT, sgPKCl/i shNT and sgPKCl/i shPHGDH. Methyl blue (MB) staining for total genomic DNA loading (n = 3).

[0172] Figure 7B shows Intracellular SAM levels in sgPKCl/i and sgC with stable shPHGDH or shNT, and western blot of indicated proteins (n = 3).

[0173] Figure 7C shows Violin plot of pileup score values for mapped regions of the Medip-seq in sgC and sgPKCl/i, black lines show magnification of the 0 to 100 score region with median pile up score in red.

[0174] Figure 7D shows Venn diagram of overlap between differentially methylated regions (DMR) in sgC and sgPKCl/i.

[0175] Figure 7E shows Venn diagram of overlap between DMR- sgPKCl/i and differentially expressed genes in sgPKCl/i vs sgC.

[0176] Figure 7F shows Medip-seq and qPCR ofADAMTSl and CDKN1A in sgC and sgPKCl/i stably transfected with shPHGDH or shNT (n = 3).

[0177] Figure 7G shows Venn diagram of gene overlap between DMR-sgPKCl/i and

Hypermethylated CpG regions in NEPC and DMR in High Grade PCa.

[0178] Figure 7H shows Western blot of indicated proteins in sgC and sgPKCl/i treated with 5 mM Aza (n = 3).

[0179] Figure 71 shows qPCR of indicated genes in sgC and sgPKCl/i treated with 5 pM Aza for 4 days (n = 3).

[0180] Figure 7J shows Western blot of indicated proteins in sgC and sgPKCl/i treated with Cyclo for 6 days (n = 3).

[0181] Figure 7K shows qPCR of indicated genes in sgC and sgPKCl/i treated with 2 mM Cyclo for 6 days (n = 3).

[0182] Figure 7L shows cell proliferation of sgC and sgPKCl/i with Cyclo or Aza (n = 3). [0183] Figure 7M shows Average size of PTEN KO and DKO prostate-derived organoids treated with 5 mM Aza for 4 days (n = 3).

[0184] Figure 7N shows qPCR of Ncaml in PTEN KO and DKO prostate-derived organoids treated as in (M; n = 3).

[0185] Figure 70 shows Tumor growth of xenografts of sgC shNT (n = 6), sgPKCl/i shNT (n = 5) and sgPKCl/i shPHGDH (n = 6) treated with Veh, and sgPKCl/i shNT treated with Aza (n =

4)·

[0186] Figure 7P shows Staining of 5mC and NCAM1 in sgC and sgPKCl/i xenograft tumors treated with Veh or Aza, H&E staining and quantification (n = 3).

[0187] Figure 7Q shows a diagram of the mechanism.

[0188] Figure 8A shows Oncoprint of PRKCI expression (EXP < 0) and most prevalent PCa alterations (MUT and HOMDEL) in a cohort of NEPC samples (n = 118).

[0189] Figure 8B shows GSEA of PRKCI expression with“Androgen Response” signature in a cohort of NEPC samples.

[0190] Figure 8C shows common genomic alterations in a PCa dataset, corrected for ploidy.

[0191] Figure 8D shows staining of PKCl/i and NCAM1 of prostate tumor and liver and lung metastases of TRAMP mice (n = 3).

[0192] Figure 8E shows Expression levels of PRKCI mRNA in samples from PTEN,

RB 1/PTEN KO, p53/RB 1/PTEN KO of PT (Primary Tumor), M (Metastasis) and R (Recurrence) from GSE90891 dataset.

[0193] Figure 9A shows aSMA IHC of PTEN KO (n = 5) and DKO (n = 7) prostates.

[0194] Figure 9B shows Quantification of CK5, CK8 and AR IHC staining in PTEN and DKO mice (n = 4).

[0195] Figure 9C shows qPCR analysis of indicated genes in shNT and shPKCl/i PTENKO mouse-derived prostate organoids (n = 3).

[0196] Figure 10A shows a heatmap of top differentially expressed genes in shPKCl/i vs shNT PrEC microarray from a NEPC signature. (Beltran et al 2011).

[0197] Figure 10B shows GSEA by comparison of NEPC vs PCa adenocarcinoma samples (left) and GSEA by correlation of PRKCI expression (right) using the datasets; GSE41192 and

GSE32967, and Hallmark gene set compilation.

[0198] Figure IOC shows clonogenic assay and Western blot analysis of indicated proteins in shNT or shPKCl/i LNCaP cells (n = 3).

[0199] Figure 10D shows a Sphere formation assay of shNT and shPKCl/i PC3 cells (n = 3).

[0200] Figure 10E shows qPCR of indicated genes in shNT and shPKCl/i PC3 cells (n = 3). [0201] Figure 10F shows cell proliferation of shNT and shPKCl/i DU145 cells (n = 3).

[0202] Figure 10G shows qPCR of SYP and Western blot analysis of indicated proteins in shNT and shPKCl/i DU145 cells (n = 3).

[0203] Figure 10H shows a clonogenic assay of FLAG-Empty and FLAG-PKCl/i PC3 cells (n = 3).

[0204] Figure 101 shows cell proliferation of FLAG-Empty and FLAG-PKCl/i DU 145 cells (n = 3).

[0205] Figure 10J shows qPCR of SYP and Western blot analysis of indicated proteins in FLAG-Empty and FLAG- PKCl/i DU145 cells (n= 3).

[0206] Figure 10K shows Tumor growth of xenografts of sgC shNT (n = 5) and sgPKCl/i (n = 4) C42B cells treated with Enzalutamide (lOmg/kg, daily after implantation).

[0207] Figure 11A shows Investigate Gene Set results as gene overlaps (k/K) of PKCl/i- dependent genes, including gene set name, red for upregulated, blue for downregulated, p-value of overlap, and gene counts in the overlap.

[0208] Figure 11B shows Venn diagram showing list of genes downregulated in sgPKCl/i vs sgC and rescued in sgPKCl/i-R that overlap with the“Hallmark Androgen Response” gene set.

[0209] Figure 11C shows western blot analysis of indicated proteins in myc-BioID2 -Empty or myc-BioID2-PKCl/i LNCaP cells.

[0210] Figure 11D shows the site of phosphorylation by RKϋl/i in LAMTOR2 and

conservation analysis of amino acid sequence around S30 of LAMTOR2.

[0211] Figure 11E shows the Crystal structure of the human LAMTOR-RagA CTD-RagC CTD complex pseudo colored by chain with S30 of LAMTOR2 labeled in red and schematic diagram of the location of S30 of LAMTOR2 within the complex.

[0212] Figure 11F shows Western Blot of indicated proteins in membrane fractions of sgC and sgPKCl/i C42B cells.

[0213] Figure 12A shows a heatmap of ATF4 targets in sgC, sgPKCl/i and sgPKCl/i-R C42B cells (all q-values <0.05).

[0214] Figure 12B shows Western blot of indicated proteins in LNCaP cells transfected with anti PKCl/i or control (C) siRNA (n = 3).

[0215] Figure 12C shows Western blot of indicated proteins in sgC, sgPKCl/i and sgPKCl/i-R C42B cells (n = 3).

[0216] Figure 12D shows alignment results in the exon 4 of XBP1 of sgC and sgPKCl/i C42B cells. [0217] Figure 12E shows Western blot of indicated proteins in sgC or sgPKCl/i C42B cells transfected with siRaptor or control siRNA (n= 2).

[0218] Figure 12F shows pathway analysis (IP A) of predicted ATF4 targets that are upregulated in sgPKCl/i vs sgC C42B cells.

[0219] Figure 12G shows qPCR of indicated genes in LNCaP cells transfected with siPKCl/i or control siRNA (n = 3).

[0220] Figure 12H shows Heatmap representation of differentially expressed ATF4 -dependent genes in shPKCl/i vs shNT PrEC cells.

[0221] Figure 121 shows qPCR analysis of E2F1 expression in sgPKCl/i and sgC cells with anti PKCl/i or control siRNA. Western Blot of cMYC, PKCl/i, and Actin. (n = 3).

[0222] Figure 12J shows intracellular quantification of polar metabolites in sgC and sgPKCl/i C42B at 24 hr after media change.

[0223] Figure 12K shows quantification of extracellular glucose and lactate in sgC and sgPKCl/i C42B cells at the indicated time points normalized to protein amount (n = 4).

[0224] Figure 12L shows fraction of labeled [U- ¹³ C ₆ ]Glucose-derived intracellular metabolite at 24 hr in sgC, sgPKCl/i, and sgPKCl/i-R C42B cells (n = 3). SGOCP metabolites colored red (n = 3).

[0225] Figure 12M shows Cellular efflux of labeled [U- ¹³ C ₆ ]Glucose-derived intracellular serine and glycince in sgC, sgPKCl/i, and sgPKCl/i-R C42B cells (n = 3).

[0226] Figure 13A shows staining of PKCl/i, ATF4, NCAM1 and SYP and H&E in a PCa cohort of Adenocarcinoma (n = 7) and NEPC (n = 14).

[0227] Figure 13B shows a Patient cohort description with histological classification, NCAM1 and SYP marker information, PKCl/i expression quantification (as normalized values), %

ATF4+ nuclei, and tumor type.

[0228] Figure 14A shows percentage of labeled M+l methyl-cytosine (mCyt) to total methyl- cytosine from [methyl- ¹³ C]Methionine in sgC and sgPKCl/i C42B cells with or without serine (n = 3).

[0229] Figure 14B shows Methyl -cytosine to cytosine rations from GC-MS analysis of sgC and sgPKCl/i C42B cells (n = 3).

[0230] Figure 14C shows Intracellular SAM levels in sgC and sgPKCl/i C42B cells treated with 50 nM Rapamycin for 48 hr (n = 4).

[0231] Figure 14D shows Intracellular SAM levels in sgC and sgPKCl/i C42B cells stably transfected with shATF4 or shNT (n = 4). [0232] Figure 14E shows methylation profiles of sgC and sgPKCl/i Medip-seq data across all RefSeq gene coordinates with k-means (n=5) clustering.

[0233] Figure 14F shows Methylation profiles of sgC and sgPKCl/i Medip-seq data across upregulated genes (by comparing sgPKCl/i vs sgC) clustered by k-means (n=5) and transcription factor enrichment results showed for clusters with defined peaks.

[0234] Figure 14G shows Methylation profiles of sgC and sgPKCl/i Medip-seq data across downregulated genes (by comparing sgPKCl/i vs sgC) clustered by k-means (n=5) and transcription factor enrichment results showed for clusters with defined peaks.

[0235] Figure 14H shows Pathway analysis shared by DMR-sgPKCl/i, Hypermethylated CpG regions in NEPC and DMR in High Grade PCa.

[0236] Figure 141 shows Diagram of metabolic pathways: Glycolysis, TCA, Serine and Glycine synthesis, one-carbon cycle and SAM synthesis. In red are inhibitors used in this study.

[0237] Figure 15 shows a schematic of the effect of downregulation of PKCl/i has on the mTORCl/ATF4/PHGDH Axis and the development of NEPC.

[0238] Figure 16A shows hyaluronan staining of prostate from prostate of WT mice and from prostate tumors from DKO ^IEC mice (n = 5).

[0239] Figure 16B shows CD44 staining of prostate sections from PTEN KO and DKO mice (n = 5).

DETAILED DESCRIPTION OF THE INVENTION

[0240] Described herein are methods and compositions for treating, preventing the onset of, and diagnosing subsets of diseases based on the expression levels of particular biomarkers. Further provided are models of human neuroendocrine prostate cancer, including, but not limited to animal models, as well as methods of producing the models disclosed herein. Various metabolic pathways are elucidated herein to validate the various methods and compositions.

[0241] As used herein,“hypermethylation” refers to aberrant expression of DNA (cytosine-5-)- methyl -transferase 1 (DNMT1) and other DNMTs that methylate genomic DNA involved in processes of gene inactivation, chromatin organization, X chromosome inactivation, and genomic imprinting.

[0242] As used herein, an“appropriate” expression level of a biomarker can refer to either a “low” expression level as compared to the expression level of the particular biomarker in a subject not suffering from the disease, condition, or subset of disease or condition of interest or a “high” expression level as compared to the expression level of the particular biomarker in a subject not suffering from the disease, condition, or subset of disease or condition of interest. The appropriate expression level of PKCl/i, AR-target, and NEPC repressors to indicate that a subject is suffering from or is likely to suffer from NEPC is lower than reference levels. The appropriate expression level of ATF4, PHGDH, mTORCl, NEPC biomarkers, and

phosphorylation of Threonine 37 and Threonine 46 of 4EBP1 to indicate that a subject is suffering from or is likely to suffer from NEPC is higher than reference levels. The appropriate expression level of hyaluronan and CD44 to indicate that a subject is suffering from or is likely to suffer from NEPC is higher than reference levels.

[0243] Described herein are metabolic pathways that result in the onset and/or progression of diseases and subsets of diseases. In some embodiments, the onset and/or progression of the disease or subset of disease results from hypermethylation. In some embodiments, the metabolic pathways described herein result in cell proliferation. In some embodiments, the metabolic pathways described herein result in inflammation.

[0244] A current problem in immunology is that increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence particular subsets of diseases, including, but not limited to neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. As described herein, protein kinase C PKCl/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis (SGOCP) through an mTORCl/ATF4- driven pathway. This metabolic reprogramming increases intracellular SAM levels to support cell proliferation and epigenetic changes that favor the development of NEPC characteristics.

Described herein is a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, and various methods and compositions that mechanistically act on said metabolic pathway.

[0245] Therapy resistance is a major clinical problem in the treatment of prostate cancer (PCa), in which although androgen deprivation therapy (ADT) has proven effective for its early management, tumors become resistant to ADT leading to a lethal outcome known as castration resistant (CRPC). As a result, increasingly potent second-generation androgen receptor (AR)- targeted therapies, such as enzalutamide and abiraterone, have been successfully implemented as a second line of therapy. However, a sustained response to these agents is also limited and nearly all treated individuals will ultimately progress and develop resistance. One major form of tumor relapse involves the reactivation of the AR axis through several different mechanisms.

Alternatively, disease progression may arise in the absence of a functional AR, as an extremely aggressive, highly proliferative, and metastatic PCa variant, termed NEPC.

[0246] As described herein, reduced levels of the atypical protein kinase C, PKCl/i (encoded by the gene PRKC1 ), could be a determinant event in the mechanisms leading to NEPC differentiation. Further as described herein, loss of PKCl/i plays a key role in driving NEPC progression to unveil potential metabolic non-oncogenic vulnerabilities that are susceptible to therapeutic intervention during NEPC progression.

Various Biomarkers for NEPC

[0247] Described herein, comparative bioinformatics analysis of NEPC vs. prostate

adenocarcinoma human samples by Gene Set Analysis (GSEA) showed a significant enrichment in the“mTORCl Signaling” signature in NEPC (Figure 6A). Gene expression analysis of datasets of enzalutamide resistant C42B cells (Figure 6B), as well as of an enzalutamide resistant human metastasis, profiled before and after therapy (Figure 6C), demonstrated the upregulation of SGOCP enzymes concomitant with downregulation of PKCl/i in the resistant samples

(Figures 6B and 6C). Interrogation of a collection of tumor-derived organoids of advanced PCa, revealed the downregulation of PKCl/i concomitant to an increase in NEPC markers and SGOCP enzymes in the organoid line derived from a treatment-induced case of NEPC (PCa4) (Figure 6D). Further bioinformatics interrogation of a human NEPC dataset showed increased mRNA expression of SGOCP enzymes as compared to adenocarcinoma samples (Figure 6E). Immunohistochemistry analysis of adenocarcinoma and NEPC tissues from a cohort of 19 patients (Figures 13A and 13B), showed higher mTORCl activity, as determined by p4EBPl (Thr37/46) staining to detect the phosphorylation of Threonine 37 and Threonine 46,

concomitant with increased expression of PHGDH, in NEPC as compared to adenocarcinoma (Figures 6F, 6G, 13A and 13B). Notably, areas of NEPC showed much stronger nuclear ATF4 staining than adenocarcinoma lesions (Figures 6H, 13A and 13B). These results demonstrate the clinical relevance of the hyperactivation of the mTORCl /ATF4/PHGDH axis, which occurs in de novo NEPC as well as in NEPC lesions that arise after treatment.

Methods of Diagnosis and Prognosis of NEPC in a Subject

[0248] Aspects disclosed herein provide methods of diagnosing, characterizing, and/or prognosing NEPC in a subject, provided certain biomarkers are detected in a biological sample obtained from the subject. The biological sample may be obtained directly or indirectly from the subject. In some embodiments, the biological sample comprises a tissue biopsy from the prostate, tumor, or both. In some instances, the tissue biopsy is a needle biopsy, a surgical biopsy or an aspiration biopsy. In some instances the fine needle biopsy comprises a fine need aspiration (FNA). In some embodiments, the biological sample comprises whole blood, sera, or plasma. In some instances, the subject is a mammal. In some instances, the subject is a mouse, rat, monkey, or rabbit. In some instances, the subject is a human. In some instances, the subject is suffering from, or has symptoms related to, a disease or condition. In some instances, the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, or small cell prostate cancer. Non-limiting examples of prostate cancers are characterized by acinar adenocarcinoma. Non-limiting examples of prostate cancers are characterized by ductal adenocarcinoma. In some instances, the disease or condition comprises a cancer of the intestine. Non-limiting examples of cancer of the intestine include adeonocarcinoma, sarcoma, leiomyosarcoma, carcinoid tumors, gastrointestinal stromal tumor, and lymphoma.

[0249] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of PKCl/i; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of PKCl/i detected in the biological sample obtained from the subject are low, as compared to the levels of expression of PKCl/i in an individual that does not have NEPC. The levels of expression of PKCl/i may be detected by measuring the expression of the gene PRKCL , or gene products expressed from the gene PRKCL In some embodiments, PKCl/i expression comprises ribonucleic acid (RNA) expression. In some embodiments, PKCl/i expression comprises protein expression. In some embodiments, PKCl/i expression comprises deoxyribonucleic acid (DNA) expression. A“low” level of expression of PKCl/i is a statistically significant amount of expression below the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof. In some embodiments, the levels of expression of PKCl/i are performed using the methods of detection disclosed herein. In some instances, detecting low levels of expression ofPKCl/i in a biological sample obtained from the subject is indicative that the subject has increased DNA methylation and cell proliferation.

[0250] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of ATF4; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of ATF4 detected in the biological sample obtained from the subject are high, as compared to the levels of expression of ATF4 in an individual that does not have NEPC. The levels of expression of ATF4 may be detected by measuring the expression of the gene ATF4, or gene products expressed from the gene ATF4. In some embodiments, ATF4 expression comprises ribonucleic acid (RNA) expression. In some embodiments, ATF4 expression comprises protein expression.

In some embodiments, ATF4 expression comprises deoxyribonucleic acid (DNA) expression. A “high” level of expression of ATF4 is a statistically significant amount of expression be high the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0251] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of PHGDH; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of PHGDH detected in the biological sample obtained from the subject are high, as compared to the levels of expression of PHGDH in an individual that does not have NEPC. The levels of expression of PHGDH may be detected by measuring the expression of the gene PHGDH , or gene products expressed from the gene PHGDH. In some embodiments, PHGDH expression comprises ribonucleic acid (RNA) expression. In some embodiments, PHGDH expression comprises protein expression. In some embodiments, PHGDH expression comprises deoxyribonucleic acid (DNA) expression. A“high” level of expression of PHGDH is a statistically significant amount of expression be high the level of expression in a normal, or non- diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0252] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of mTORCl; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of mTORCl detected in the biological sample obtained from the subject are high, as compared to the levels of expression of mTORCl in an individual that does not have NEPC. The levels of expression of mTORCl may be detected by measuring the phosphorylation of Threonine 37 and Threonine 46 of 4EBP1. In some embodiments, mTORCl expression comprises ribonucleic acid (RNA) expression. In some embodiments, mTORCl expression comprises protein expression hi some embodiments, mTORCl expression comprises deoxyribonucleic acid (DNA) expression. A“high” level of expression of mTORCl is a statistically significant amount of expression be high the level of expression in a normal, or non- diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0253] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of NEPC biomarkers; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of NEPC biomarkers detected in the biological sample obtained from the subject are high, as compared to the levels of expression of NEPC biomarkers in an individual that does not have NEPC. The levels of expression of NEPC biomarkers may be detected by measuring the expression of the genes SYP, EN02 , NCAM1 , and CHGA , or gene products expressed from the genes SYP, EN02 , NCAM1 , and CHGA. In some embodiments, NEPC biomarkers expression comprises ribonucleic acid (RNA) expression. In some embodiments, NEPC biomarkers expression comprises protein expression. In some embodiments, NEPC biomarkers expression comprises deoxyribonucleic acid (DNA) expression. A“high” level of expression of NEPC biomarkers is a statistically significant amount of expression below the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0254] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of NEPC repressors; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of NEPC repressors detected in the biological sample obtained from the subject are low, as compared to the levels of expression of NEPC repressors in an individual that does not have NEPC. The levels of expression of NEPC repressors may be detected by measuring the expression of the gene REST, or gene products expressed from the gene REST. In some embodiments, NEPC repressors expression comprises ribonucleic acid (RNA) expression. In some embodiments, NEPC repressors expression comprises protein expression. In some embodiments, NEPC repressors expression comprises deoxyribonucleic acid (DNA) expression. A“low” level of expression of NEPC repressors is a statistically significant amount of expression below the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0255] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of an AR-target; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of the AR-target detected in the biological sample obtained from the subject are low, as compared to the levels of expression of the AR-target in an individual that does not have NEPC. The levels of expression of AR-target may be detected by measuring the expression of the gene KLK3 , or gene products expressed from the gene KLK3. In some embodiments, the AR- target expression comprises ribonucleic acid (RNA) expression. In some embodiments, the AR- target expression comprises protein expression. In some embodiments, the AR-target expression comprises deoxyribonucleic acid (DNA) expression. A“low” level of expression of the AR- target is a statistically significant amount of expression below the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of DNA Methyltransferase, ATF4, PHGDH, mTORCl, or a combination of inhibitors thereof.

[0256] Aspects disclosed herein provide methods of diagnosing a subtype of cancer, including but not limited to, prostate cancer, in a subject in need thereof, the method comprising: a) obtaining a biological sample from a subject in need thereof; b) subjecting the biological sample to an assay suitable to detect levels of expression of hyaluronan or CD44; and c) diagnosing the subject with a subtype of prostate cancer, including but not limited to, NEPC, provided the levels of expression of hyaluronan or CD44 detected in the biological sample obtained from the subject are high, as compared to the levels of expression of hyaluronan or CD44 in an individual that does not have NEPC. The levels of expression of hyaluronan or CD44 may be detected by measuring the expression of the gene HAS1 , HAS2 , HAS 3, or ( 1)44 or gene products expressed from the gene HAS I, HAS2 , HAS 3, or CD44. In some embodiments, hyaluronan expression comprises ribonucleic acid (RNA) expression oiHASl , HAS2 , or HAS3. In some embodiments, hyaluronan expression comprises protein expression of HAS1, HAS2, or HAS3. In some embodiments, hyaluronan expression comprises deoxyribonucleic acid (DNA) expression of HAS1 , HAS2 , or HAS3. In some embodiments, hyaluronan expression comprises polysaccharide. In some embodiments, CD44 expression comprises ribonucleic acid (RNA) expression. In some embodiments, CD44 expression comprises protein expression. In some embodiments, CD44 expression comprises deoxyribonucleic acid (DNA) expression. A“high” level of expression of hyaluronan or CD44 is a statistically significant amount of expression above the level of expression in a normal, or non-diseased, individual. In some embodiments, a subject diagnosed with NEPC according to the present methods is administered an inhibitor of hyaluronan, hyaluronan synthase, CD44, or a combination of inhibitors thereof.

[0257] Aspects disclosed herein provide methods of evaluating a biological sample obtained from the subject for the presence, absence, and/or quantity of a nucleic acid sequence from a gene comprising REST , KLK3 , SYP, EN02 , NCAM1 , CHGA , PRKCI, HAS1 , HAS2, HAS3 , and/or CD44 , or gene product expressed from the gene comprising REST, KLK3 , SYP, EN02, NCAM1, CHGA, PRKCI, HAS1, HAS2, HAS3, and/or CD44. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA). In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector- expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

[0258] Disclosed herein, in some embodiments, are nucleic acid-based detection assays useful for the detection of a presence, absence, and/or quantity of a nucleic acid sequence from a gene comprising REST, KLK3, SYP, EN02, NCAM1, CHGA, PRKCI, HAS1 , HAS2 , HAS3, and/or CD44 , or gene product expressed from the gene comprising REST, KLK3, SYP, EN02, NCAM1, CHGA, PRKCI, HAS1, HAS2, HAS3, and/or CD44,. In some instances, the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, or sequencing. In some embodiments, the sequencing technique comprises next generation sequencing. In some embodiments, the methods involve a hybridization assay such as fluorogenic qPCR (e.g, TaqMan™ or SYBR green), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more genes disclosed herein is used. In some instances, the nucleic acid probe is specific to REST, KLK3, SYP, EN02, NCAM1, CHGA, PRKCI, HAS1, HAS2, HAS3, and/or CD44, or gene product expressed from the gene comprising PEST, KLK3, SYP, EN02, NCAM1, CHGA, PRKCI, HAS1 , HAS2 , HAS3, and/or CD44.

[0259] Disclosed herein, in some embodiments, are methods of detecting a gene of an individual by subject a sample obtained from the individual to a nucleic acid amplification assay. In some instances, the amplification assay comprises polymerase chain reaction (PCR), qPCR, self- sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any suitable other nucleic acid amplification technique. A suitable nucleic acid amplification technique is configured to amplify a region of a nucleic acid sequence comprising one or more genes, or gene expression products thereof, disclosed herein. In some instances, the amplification assays requires primers. The nucleic acid sequence for the gene, or gene expression products thereof, known or provided herein is sufficient to enable one of skill in the art to select primers to amplify any portion of the gene or genetic variants. A DNA sample suitable as a primer may be obtained, e.g, by polymerase chain reaction (PCR) amplification of genomic DNA, fragments of genomic DNA, fragments of genomic DNA ligated to adaptor sequences or cloned sequences. A person of skill in the art would utilize computer programs to design of primers with the desired specificity and optimal amplification properties, such as Oligo version 7.0 (National Biosciences). It will be apparent to one skilled in the art that controlled robotic systems are useful for isolating and amplifying nucleic acids and can be used. [0260] In some embodiments, detecting the presence or absence and/or quantity of a gene comprising REST, KLK3, SYP , EN02, NCAM1, CHGA , PRKCI , HAS1, HAS2 , HAS3, and/or CD44 , or gene expression produced expressed from the gene REST, KLK3, SYP, EN02, NCAM1, CHGA, PRKCI, HAS1, HAS2, HAS3, and/or CD44, comprises sequencing genetic material obtained from a biological sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g, Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g, modern sequencing technologies such as Illumina sequencing (e.g, Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD

sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0261] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20,

25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0262] In some embodiments, detecting the presence or absence and/or quantity of a gene comprising REST, KLK3, SYP , EN02, NCAM1 , CHGA , PRKC1 , HASP HAS2 , HAS3, and/or CD44 , or gene expression produced expressed from the gene comprising RESJ\ KLK3 , SYP, EN02 , NCAMp CHGA , PRKCI, HASP HAS2, HAS3, and/or CD44, comprises hybridizing a probe or reporting sequence to a target nucleic acid described herein. Examples of molecules that are utilized as probes include, but are not limited to, RNA and DNA. In some embodiments, the term“probe” with regards to nucleic acids, refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxaazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy- X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include 1- dimethylaminonaphthyl-5-sulfonate, l-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6- naphthalene sulfonate, 5-(2'-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS). Exemplary coumarins include, e.g, 3 -phenyl -7-isocyanatocoumarin; acridines, such as 9- isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g, indodi carbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3'-ethyl-5,5'-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H- Xantheno[2,3, 4-ij : 5,6, 7-i'j ']diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l- pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17- octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label. [0263] In some instances, primers and/or probes described herein for detecting a target nucleic acid are used in an amplification reaction. In some instances, the amplification reaction is qPCR. An exemplary qPCR is a method employing a TaqMan™ assay.

[0264] In some instances, qPCR comprises using an intercalating dye. Examples of intercalating dyes include SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin. In some instances, the intercalating dye is SYBR.

[0265] In some instances, a number of amplification cycles for detecting a target nucleic acid in an amplification assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.

[0266] In one aspect, the methods provided herein for determining the presence, absence, and/or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR. In an exemplary method, genetic material is obtained from a sample of a subject, e.g ., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis.

In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially and one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction, the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.

[0267] In some embodiments, detecting and quantifying soluble protein levels of PKCl/i, ATF4, PHGDH, mTORCl, hyaluronan synthase, and/or CD44 in a subject by detecting and quantifying said levels from a biological sample obtained from the subject are provided. PKCl/i, ATF4, PHGDH, mTORCl, hyaluronan synthase, and/or CD44 may be detected by use of an antibody- based assay, where an antibody specific to PKCl/i, ATF4, PHGDH, mTORCl, hyaluronan synthase, and/or CD44 ( e.g ., anti- PKCl/i, anti- ATF4, anti- PHGDH, anti- mTORCl, anti- HAS1, anti-HAS2, anti-HAS3, and/or anti-CD44 antibodies) is utilized. For antibody-based detection methods, the antibody may bind to any region of PKCl/i, ATF4, PHGDH, mTORCl hyaluronan synthase, and/or CD44. An exemplary method of analysis comprises performing an enzyme-linked immunosorbent assay (ELISA). The ELISA assay may be a sandwich ELISA or a direct ELISA. Another exemplary method of analysis comprises a single molecule array, e.g., Simoa. Other exemplary methods of detection include immunohistochemistry and lateral flow assay.

[0268] In some cases, ATF4 and/or PHGDH protein may be detected by detecting binding between ATF4 and/or PHGDH and other binding partners of ATF4 and/or PHGDH. Methods of analysis of binding between ATF4 and/or PHGDH, as well as with other binding partners comprise performing an assay in vivo or in vitro, or ex vivo. In some instances, the assay may comprise co-immunoprecipitation (co-IP), pull-down, crosslinking protein interaction analysis, labeled transfer protein interaction analysis, or Far-western blot analysis, FRET based assay, including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.

[0269] In some embodiments, the methods and biomarkers described herein can be administered on a subject already suffering from a disease or condition including, but not limited to prostate cancer. In these embodiments, the methods and biomarkers described herein determine if the subject suffering from a disease or condition will develop a subset of said disease or condition, including but not limited to NEPC.

Disease Subset Therapy

[0270] The present disclosure provides that treatment of subjects with a subset of a disease including, but not limited to NEPC with a combination of an AR-targeting therapy, including, but not limited to Enzalutamide, and an inhibitor to DNA methyltransferase (DNMT) caused regression in tumors and cell proliferation. Whereas, treatment of NEPC subjects with AR- targeting monotherapy results in acquired resistance by cancer cells to the therapy, an AR- targeting therapy, including, but not limited to Enzalutamide caused regression in serrated tumors when co-administration of an inhibitor of DNMT, which serves inhibit DNA hypermethylation and cancer cells’ ability to acquire resistance to the AR-therapy. Further disclosed, decreased expression of PKCl/i leads to hypermethylation through the mTORCl/ATF4/PHGDH axis and increased serine metabolism (SGOCP) suggests that the interrupting the interaction between the mTORCl/ATF4/PHGDH axis and SGOCP metabolism may provide a suitable therapeutic solution for treating a subset of a disease or condition, including, but not limited to NEPC. In addition, as the increased level of hyaluronan in the stroma could further support tumor growth through the interaction with its receptor CD44 to fuel neuroendocrine prostate tumors, interfering with hyaluronan, CD44, or the interaction between hyaluronan and CD44 could provide a solution for treating a subset of a disease or condition, including, but not limited to NEPC.

[0271] Aspects disclosed herein provide methods of treating a disease or a condition, or a subtype of the disease or condition, in a subject by administering to the subject a therapeutically effective amount of one or more of the therapeutic agents disclosed herein. In some instances, the disease or condition comprises prostate cancer, castration resistant prostate cancer,

neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments the subject is a mouse, rat, monkey, or rabbit.

Therapeutic agents

[0272] Aspects disclosed herein provide methods of treating a disease or condition, or a subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of a therapeutic agent disclosed herein, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to reference levels of expression of said biomarkers in an individual who does not have the disease or condition. In some embodiments, the therapeutic agent is effective to reduce or increase the activity or expression of a therapeutic target. Non-limiting examples of therapeutic targets include DNA methyltransferase, ATF4, PHGDH, mTORCl, hyaluronan, and CD44. Non limiting examples of therapeutic agents include agonists and antagonists of the above therapeutic targets.

Treatment by AR-target therapy and DNMT Inhibitor

[0273] Aspects disclosed herein provide methods of treating a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a DNMT inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a DNMT inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0274] In some embodiments, the AR-target therapy and a DNMT inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

[0275] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises ALOsiRNA.

[0276] In some embodiments, the inhibitor of DNA methyltransferase directly inhibits DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antagonist of DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an anti- DNA methyltransferase antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the DNA methyltransferase molecule. In some

embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises decitabine (Aza). In some embodiments, the DNA methyltransferase inhibitor comprises DNMTsiRNA. [0277] In some embodiments, the inhibitor of DNA methyltransferase indirectly inhibits DNA methyltransferase.

[0278] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase activity or expression comprises an inhibitor of SGOCP enzyme activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises an antagonist of SGOCP enzyme. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises an anti- SGOCP enzyme antibody. In some

embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the SGOCP enzyme molecule. In some embodiments, the SGOCP enzyme inhibitor comprises SGOCP enyzmesiRNA.

[0279] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase activity or expression comprises an inhibitor of S-Adenosyl methionine (SAM) activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antagonist of SAM. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an anti- SAM antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the SAM molecule. In some embodiments, the SAM inhibitor comprises SAMsiRNA. In some embodiments, the inhibitor of SAM inhibits methionine

adenosyltransferase 2A (Mat2A). In some embodiments, the inhibitor of SAM binds to the Mat 2A— Mat2B complex. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises cycloleucine (Cyclo).

Treatment by AR-target therapy and ATF4 Inhibitor

[0280] Aspects disclosed herein provide methods of treating a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and an ATF4 inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and an ATF4 inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0281] In some embodiments, the AR-target therapy and an ATF4 inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, about 21 hours prior to administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to

administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises ALOsiRNA.

[0282] In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antagonist of ATF4. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an anti- ATF4 antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the ATF4 molecule. In some embodiments, the ATF4 inhibitor comprises ATF4siRNA.

Treatment by AR-target therapy and PHGDH Inhibitor

[0283] Aspects disclosed herein provide methods of treating a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a PHGDH inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a PHGDH inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0284] In some embodiments, the AR-target therapy and a PHGDH inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises ALOsiRNA.

[0285] In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antagonist of PHGDH. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an anti- PHGDH antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the PHGDH molecule. In some embodiments, the PHGDH inhibitor comprises

PHGDHsiRNA. Treatment by AR-target therapy and mTORCl Inhibitor

[0286] Aspects disclosed herein provide methods of treating a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a mTORCl inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a mTORCl inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0287] In some embodiments, the AR-target therapy and a mTORCl inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises AVXJsiRNA.

[0288] In some embodiments, the method is performed, wherein the inhibitor of

mTORCl activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an antagonist of mTORCl. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an anti- mTORCl antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the mTORCl molecule. In some embodiments, the mTORCl inhibitor comprises mTORCl siRNA.

[0289] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase is selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of PHGDH, an inhibitor of SGOC enzyme, and an inhibitor of SAM activity.

[0290] In some embodiments, the method is performed, wherein the inhibitor is a combination of inhibitors selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

Treatment by AR-target therapy and hyaluronan or CD44 Inhibitor

[0291] Aspects disclosed herein provide methods of treating a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a hyaluronan or CD44 inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a hyaluronan or CD44 inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0292] In some embodiments, the AR-target therapy and a hyaluronan or CD44 inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to administration of AR- targeting therapy to the same subject to about 3 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to

administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 hour prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, about 21 hours prior to administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to

administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR- targeting therapy to the same subject to about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to

administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to

administration of AR-targeting therapy to the same subject to about 12 weeks prior to

administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR- targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

[0293] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises ALOsiRNA.

[0294] In some embodiments, hyaluronan is synthesized by hyaluronan synthase encoded by HAS1 , HAS2 , or HAS 3 gene. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a peptide. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antagonist of HAS1, HAS2, HAS3, or CD44. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an anti-HASl, anti-HAS2, anti-HAS3, or anti-CD44 antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the HAS1, HAS2, HAS3, or CD44 molecule. In some embodiments, the hyaluronan or CD44 inhibitor comprises HAS1 siRNA, HAS2 siRNA, HAS3 siRNA, or CD44 siRNA. In some embodiments, the method is performed, wherein the inhibitor is a combination of hyaluronan and CD44 inhibitor.

Method of Preventing the Onset of a Subset of a Disease

[0295] The present disclosure provides that treatment of subjects suffering from a disease including, but not limited to prostate cancer with a combination of an AR-targeting therapy, including, but not limited to Enzalutamide, and an inhibitor to DNA methyltransferase (DNMT) prevented the onset of NEPC. Whereas, treatment of prostate cancer subjects with AR-targeting monotherapy results in acquired resistance by cancer cells to the therapy and eventual development of NEPC, an AR-targeting therapy, including, but not limited to Enzalutamide caused regression in tumors when co-administration of an inhibitor of DNMT, which serves inhibit DNA hypermethylation and cancer cells’ ability to acquire resistance to the AR-therapy. Further disclosed, decreased expression of PKCl/i leads to hypermethylation through the mTORCl/ATF4/PHGDH axis and increased serine metabolism (SGOCP) suggests that the interrupting the interaction between the mTORCl/ATF4/PHGDH axis and SGOCP metabolism may provide a suitable therapeutic solution for preventing the onset of a subset of a disease or condition, including, but not limited to NEPC.

[0296] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or a condition, or a subtype of the disease or condition, in a subject by administering to the subject a therapeutically effective amount of one or more of the therapeutic agents disclosed herein. In some instances, the disease or condition comprises prostate cancer, castration resistant prostate cancer, neuroendocrine prostate cancer, transitional cell (or urothelial) prostate cancer, squamous cell prostate cancer, small cell prostate cancer, or a combination thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments the subject is a mouse, rat, monkey, or rabbit.

Therapeutic agents

[0297] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or a subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of a therapeutic agent disclosed herein, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to reference levels of expression of said biomarkers in an individual who does not have the disease or condition. In some embodiments, the therapeutic agent is effective to reduce or increase the activity or expression of a therapeutic target. Non-limiting examples of therapeutic targets include DNA methyltransferase, ATF4, PHGDH, mTORCl, hyaluronan, and CD44. Non-limiting examples of therapeutic agents include agonists and antagonists of the above therapeutic targets.

Prevention by AR-target therapy and DNMT Inhibitor

[0298] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a DNMT inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a DNMT inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0299] In some embodiments, the AR-target therapy and a DNMT inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the DNMT inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

[0300] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises AVXJsiRNA.

[0301] In some embodiments, the inhibitor of DNA methyltransferase directly inhibits DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an antagonist of DNA methyltransferase. In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an anti- DNA methyltransferase antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the DNA methyltransferase molecule. In some

embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises decitabine (Aza). In some embodiments, the DNA methyltransferase inhibitor comprises DNMTsiRNA.

[0302] In some embodiments, the inhibitor of DNA methyltransferase indirectly inhibits DNA methyltransferase.

[0303] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase activity or expression comprises an inhibitor of SGOCP enzyme activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SGOC enzyme activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises an antagonist of SGOCP enzyme. In some embodiments, the method is performed, wherein the inhibitor of SGOCP enzyme activity or expression comprises an anti- SGOCP enzyme antibody. In some

embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the SGOCP enzyme molecule. In some embodiments, the SGOCP enzyme inhibitor comprises SGOCP enzyme siRNA.

[0304] In some embodiments, the method is performed, wherein the inhibitor of DNA

methyltransferase activity or expression comprises an inhibitor of S-Adenosyl methionine (SAM) activity or expression. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an antagonist of SAM. In some embodiments, the method is performed, wherein the inhibitor of SAM activity or expression comprises an anti- SAM antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the SAM molecule. In some embodiments, the inhibitor of SAM inhibits Methionine Adenosyltransferase 2A (MAT2A). In some embodiments, the inhibitor of SAM binds to the MAT2A— MAT2B complex. In some embodiments, the method is performed, wherein the inhibitor of SAM production comprises cycloleucine (Cyclo).

Prevention by AR-target therapy and ATF4 Inhibitor

[0305] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and an ATF4 inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and an ATF4 inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0306] In some embodiments, the AR-target therapy and an ATF4 inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the ATF4 inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to

administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises AVXJsiRNA.

[0307] In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an antagonist of ATF4. In some embodiments, the method is performed, wherein the inhibitor of ATF4 activity or expression comprises an anti- ATF4 antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the ATF4 molecule. In some embodiments, the ATF4 inhibitor comprises ATF4siRNA.

Prevention by AR-target therapy and PHGDH Inhibitor

[0308] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a PHGDH inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a PHGDH inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0309] In some embodiments, the AR-target therapy and a PHGDH inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at least about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the PHGDH inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises AVXJsiRNA.

[0310] In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an antagonist of PHGDH. In some embodiments, the method is performed, wherein the inhibitor of PHGDH activity or expression comprises an anti- PHGDH antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the PHGDH molecule. In some embodiments, the PHGDH inhibitor comprises

PHGDHsiRNA.

Prevention by AR-target therapy and mTORC1 Inhibitor

[0311] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a mTORCl inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a mTORCl inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0312] In some embodiments, the AR-target therapy and a mTORCl inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject to about 3 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to

administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 hour prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR- targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 2 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to

administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at least about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the mTORCl inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

In some embodiments, the method is performed, wherein the androgen receptor (AR)-targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some

embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises ALOsiRNA.

[0313] In some embodiments, the method is performed, wherein the inhibitor of

mTORCl activity or expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an antagonist of mTORCl. In some embodiments, the method is performed, wherein the inhibitor of mTORCl activity or expression comprises an anti- mTORCl antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the mTORCl molecule. In some embodiments, the mTORCl inhibitor comprises mTORCl siRNA. [0314] In some embodiments, the method is performed, wherein the inhibitor of DNA methyltransferase is selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of PHGDH, an inhibitor of SGOC enzyme, and an inhibitor of SAM activity.

[0315] In some embodiments, the method is performed, wherein the inhibitor is a combination of inhibitors selected from the group comprising an inhibitor of DNA methyltransferase, an inhibitor of ATF4, an inhibitor of PHGDH, and an inhibitor of mTORCl.

Prevention by AR-target therapy and hyaluronan or CD44 inhibitor

[0316] Aspects disclosed herein provide methods of preventing the onset of a subset of a disease or condition, or subtype of a disease or condition, in a subject by administering to the subject a therapeutically effective amount of an AR-target therapy and a hyaluronan or CD44 inhibitor, provided appropriate levels of expression of biomarkers are detected in a biological sample obtained from the subject, as compared to levels of expression of biomarkers in an individual who does not have the disease or condition. Disclosed herein, in certain embodiments, are methods for inhibiting or reducing tumor cell proliferation in a subject suffering from a disease or condition, comprising: a) identifying the subject as having the appropriate levels of expression of biomarkers, as compared to the levels of expression of biomarkers in an individual who does not have the disease or condition; and b) administering to the subject a therapeutically effective amount of an AR-target therapy and a hyaluronan or CD44 inhibitor. A subject may be identified as having appropriate levels of expression of biomarkers using any of the methods of detection disclosed herein.

[0317] In some embodiments, the AR-target therapy and a hyaluronan or CD44 inhibitor are administered simultaneously to the subject suffering from the disease or condition. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to administration of AR- targeting therapy to the same subject to about 3 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to

administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR- targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 1 hour prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 6 hours prior to

administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR-targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 9 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 12 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to administration of AR- targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject to about 24 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 15 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 18 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 12 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 18 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 15 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 21 hours prior to

administration of AR-targeting therapy to the same subject, about 18 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject to about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 hour prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, about 21 hours prior to

administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 hour prior to administration of AR- targeting therapy to the same subject, about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, or about 21 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 3 hours prior to administration of AR-targeting therapy to the same subject, about 6 hours prior to administration of AR-targeting therapy to the same subject, about 9 hours prior to administration of AR-targeting therapy to the same subject, about 12 hours prior to administration of AR-targeting therapy to the same subject, about 15 hours prior to administration of AR-targeting therapy to the same subject, about 18 hours prior to administration of AR-targeting therapy to the same subject, about 21 hours prior to administration of AR-targeting therapy to the same subject, or about 24 hours prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject to about 2 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 1 day prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 3 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 4 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR- targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 5 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR- targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 6 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to

administration of AR-targeting therapy to the same subject to about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 day prior to administration of AR-targeting therapy to the same subject, about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, or about 6 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 2 days prior to administration of AR-targeting therapy to the same subject, about 3 days prior to administration of AR-targeting therapy to the same subject, about 4 days prior to administration of AR-targeting therapy to the same subject, about 5 days prior to administration of AR-targeting therapy to the same subject, about 6 days prior to administration of AR-targeting therapy to the same subject, or about 7 days prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR- targeting therapy to the same subject to about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 1 week prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to

administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to

administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 6 weeks prior to

administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to

administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR- targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to

administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR- targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject to about 11 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to

administration of AR-targeting therapy to the same subject to about 12 weeks prior to

administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject to about 12 weeks prior to

administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered about 1 week prior to administration of AR- targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR- targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at least about 1 week prior to administration of AR-targeting therapy to the same subject, about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR- targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR-targeting therapy to the same subject, or about 11 weeks prior to administration of AR-targeting therapy to the same subject. In some embodiments, the hyaluronan or CD44 inhibitor is administered at most about 2 weeks prior to administration of AR-targeting therapy to the same subject, about 3 weeks prior to administration of AR-targeting therapy to the same subject, about 4 weeks prior to administration of AR-targeting therapy to the same subject, about 5 weeks prior to administration of AR-targeting therapy to the same subject, about 6 weeks prior to administration of AR-targeting therapy to the same subject, about 7 weeks prior to administration of AR-targeting therapy to the same subject, about 8 weeks prior to administration of AR-targeting therapy to the same subject, about 9 weeks prior to administration of AR-targeting therapy to the same subject, about 10 weeks prior to administration of AR- targeting therapy to the same subject, about 11 weeks prior to administration of AR-targeting therapy to the same subject, or about 12 weeks prior to administration of AR-targeting therapy to the same subject.

[0318] In some embodiments, the method is performed, wherein the androgen receptor (AR)- targeting therapy comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises a small molecule inhibitor of an androgen receptor. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises androgen depravation therapy (ADT). In some embodiments, the method is performed, wherein the AR-targeting therapy comprises

enzalutamide. In some embodiments, the method is performed, wherein the AR-targeting therapy comprises abiraterone. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the AR molecule. In some embodiments, the AR-targeting therapy comprises AVXJsiRNA.

[0319] In some embodiments, hyaluronan is synthesized by hyaluronan synthase encoded by HAS1 , HAS2 , or HAS 3 gene. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antibody, or antigen-binding fragment. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a small molecule. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises a peptide. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an antagonist of HAS1, HAS2, HAS3, or CD44. In some embodiments, the method is performed, wherein the inhibitor of hyaluronan synthase activity, hyaluronan expression, or CD44 expression comprises an anti-HASl, anti-HAS2, anti-HAS3, or anti-CD44 antibody. In some embodiments, the antibody or antibody fragment binds to 70%, 80%, 90%, or 100% of the HAS1, HAS2, HAS3, or CD44 molecule. In some embodiments, the hyaluronan or CD44 inhibitor comprises HAS1 siRNA, HAS2 siRNA, HAS3 siRNA, or CD44 siRNA. In some embodiments, the method is performed, wherein the inhibitor is a combination of hyaluronan and CD44 inhibitor.

Pharmaceutical Compositions

[0320] Pharmaceutical compositions containing an AR-targeting therapy in combination with an inhibitor of DNMT activity or expression, an inhibitor of ATF4 activity or expression, an inhibitor of PHGDH activity or expression, and/or an inhibitor of mTORCl activity or expression, another therapeutic agent, or any combinations thereof, are provided in some embodiments of this disclosure. In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy. In some embodiments, the pharmaceutical composition comprises an inhibitor of DNMT activity or expression. In some embodiments, the

pharmaceutical composition comprises an inhibitor of ATF4 activity or expression. In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy and an inhibitor of DNMT activity or expression and an inhibitor of ATF4 activity or expression. In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy and an inhibitor of PHGDH activity or expression and an inhibitor of mTORCl activity or expression.

In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy, an inhibitor of ATF4 activity or expression and an inhibitor of PHGDH activity or expression. In some embodiments, the pharmaceutical composition comprises an inhibitor of mTORCl. In some embodiments, the pharmaceutical composition comprises an inhibitor of PHGDH. In some embodiments, the pharmaceutical composition comprises an inhibitor of ATF4.

[0321] Disclosed also herein, in some embodiments, are pharmaceutical compositions containing an AR-targeting therapy in combination with an inhibitor of hyaluronan, an inhibitor of hyaluronan synthase activity or expression, and/or an inhibitor of CD44 activity or expression, another therapeutic agent, or any combinations thereof. In some embodiments, the

pharmaceutical composition comprises an inhibitor of hyaluronan. In some embodiments, the pharmaceutical composition comprises an inhibitor of CD44. In some embodiments, the pharmaceutical composition comprises an inhibitor of hyaluronan synthase activity or expression. In some embodiments, the pharmaceutical composition comprises an inhibitor of CD44 activity or expression. In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy, an inhibitor of hyaluronan synthase activity or expression, and an inhibitor of CD44 activity or expression. In some embodiments, the pharmaceutical composition comprises an AR-targeting therapy, an inhibitor of hyaluronan, and an inhibitor of CD44 activity or expression.

[0322] In some embodiments, the pharmaceutical compositions of this disclosure are prepared as solutions, dispersions in glycerol, liquid polyethylene glycols, and any combinations thereof in oils, in solid dosage forms, as inhalable dosage forms, as intranasal dosage forms, as liposomal formulations, dosage forms comprising nanoparticles, dosage forms comprising microparticles, polymeric dosage forms, or any combinations thereof. In some embodiments, a pharmaceutical composition as described herein comprises an excipient. An excipient is, in some examples, an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a chelator, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, a coloring agent.

[0323] In some embodiments an excipient is a buffering agent. Non-limiting examples of suitable buffering agents include histidine, sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. As a buffering agent, histidine, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium

glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or combinations thereof is used, in some embodiments, in a pharmaceutical composition of the present disclosure.

[0324] In some embodiments an excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol. In some examples, antioxidants further include but are not limited to EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N- acetyl cysteine. In some instances preservatives include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-a-tosyl- Phe- chloromethylketone, N-a-tosyl-Lys-chloromethylketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitor, phosphatase inhibitor, caspase inhibitor, granzyme inhibitor, cell adhesion inhibitor, cell division inhibitor, cell cycle inhibitor, lipid signaling inhibitor, protease inhibitor, reducing agent, alkylating agent, antimicrobial agent, oxidase inhibitor, or other inhibitor.

[0325] In some embodiments a pharmaceutical composition as described herein comprises a binder as an excipient. Non-limiting examples of suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium

carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone,

polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof. The binders used in a pharmaceutical formulation are, in some examples, selected from starches such as potato starch, com starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or any combinations thereof.

[0326] In some embodiments a pharmaceutical composition as described herein comprises a lubricant as an excipient. Non-limiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The lubricants that are used in a pharmaceutical formulation, in some embodiments, are be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.

[0327] In some embodiments a pharmaceutical formulation comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include, in some examples, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0328] In some embodiments a pharmaceutical composition as described herein comprises a disintegrant as an excipient. In some embodiments a disintegrant is a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth. In some embodiments a disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[0329] In some embodiments an excipient comprises a flavoring agent. Flavoring agents incorporated into an outer layer are, in some examples, chosen from synthetic flavor oils and flavoring aromatics; natural oils; extracts from plants, leaves, flowers, and fruits; and

combinations thereof. In some embodiments a flavoring agent can be selected from the group consisting of cinnamon oils; oil of wintergreen; peppermint oils; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oil such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0330] In some embodiments an excipient comprises a sweetener. Non-limiting examples of suitable sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as a sodium salt;

dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, sylitol, and the like. [0331] In some instances, a pharmaceutical composition as described herein comprises a coloring agent. Non-limiting examples of suitable color agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C). A coloring agents can be used as dyes or their corresponding lakes.

[0332] In some instances, a pharmaceutical composition as described herein comprises a chelator. In some cases, a chelator is a fungicidal chelator. Examples include, but are not limited to: ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA); a disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salt of EDTA; a barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, or zinc chelate of EDTA; trans-l,2-diaminocyclohexane-N,N,N',N'- tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; l,3-diamino-2-hydroxypropane- N,N,N',N'-tetraacetic acid; l,3-diaminopropane-N,N,N',N'-tetraacetic acid; ethylenediamine- N,N'-diacetic acid; ethylenediamine-N,N'-dipropionic acid dihydrochloride; ethylenediamine- N,N'-bis(methylenephosphonic acid) hemihydrate; N-(2-hydroxyethyl)ethylenediamine-N,N',N'- triacetic acid; ethyl enediamine-N,N,N',N'-tetrakis(methylenephosponic acid); 0,0'-bis(2- aminoethyl)ethyleneglycol-N,N,N',N'-tetraacetic acid; N,N-bis(2- hydroxybenzyl)ethylenediamine-N,N-diacetic acid; l,6-hexamethylenediamine-N,N,N',N'- tetraacetic acid; N-(2-hydroxyethyl)iminodiacetic acid; iminodiacetic acid; 1,2-diaminopropane- N,N,N',N'-tetraacetic acid; nitrilotriacetic acid; nitrilotripropionic acid; the trisodium salt of nitrilotris(methylenephosphoric acid); 7,19,30-trioxa-l,4,10,13,16,22,27,33- octaazabicyclo[l 1,11,11] pentatriacontane hexahydrobromide; or tri ethyl enetetramine- N,N,N',N" ,N' " ,N' " -hexaacetic acid.

[0333] Also contemplated are combination products that include one or more immunotherapeutic agents disclosed herein and one or more other antimicrobial or antifungal agents, for example, polyenes such as amphotericin B, amphotericin B lipid complex (ABCD), liposomal

amphotericin B (L-AMB), and liposomal nystatin, azoles and triazoles such as voriconazole, fluconazole, ketoconazole, itraconazole, pozaconazole and the like; glucan synthase inhibitors such as caspofungin, micafungin (FK463), and V-echinocandin (LY303366); griseofulvin;

allylamines such as terbinafme; flucytosine or other antifungal agents, including those described herein. In addition, it is contemplated that a peptide can be combined with topical antifungal agents such as ciclopirox olamine, haloprogin, tolnaftate, undecylenate, topical nysatin, amorolfme, butenafme, naftifme, terbinafme, and other topical agents. In some instances, a pharmaceutical composition comprises an additional agent. In some cases, an additional agent is present in a therapeutically effective amount in a pharmaceutical composition. [0334] Under ordinary conditions of storage and use, the pharmaceutical compositions as described herein comprise a preservative to prevent the growth of microorganisms. In certain examples, the pharmaceutical compositions as described herein do not comprise a

preservative. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical compositions comprise a carrier which is a solvent or a dispersion medium containing, for example, water, ethanol, polyol ( e.g ., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and/or vegetable oils, or any combinations thereof. Proper fluidity is 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. The prevention of the action of microorganisms is brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0335] For parenteral administration in an aqueous solution, for example, the liquid dosage form is suitably buffered if necessary and the liquid diluent rendered isotonic with sufficient saline or glucose. The liquid dosage forms are especially suitable for intravenous,

intramuscular, subcutaneous, intratumoral, and intraperitoneal administration. In this connection, sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage is dissolved, in certain cases, in lmL to 20 mL of isotonic NaCl solution and either added to 100 mL to 1000 mL of a fluid, e.g., sodium-bicarbonate buffered saline, or injected at the proposed site of infusion.

[0336] In certain embodiments, sterile injectable solutions is prepared by incorporating a therapeutic agent, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. The compositions disclosed herein are, in some instances, formulated in a neutral or salt form. Pharmaceutically-acceptable salts include, for example, the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups are, in some cases, derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. Upon formulation, the pharmaceutical compositions are administered, in some embodiments, in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.

[0337] In certain embodiments, a pharmaceutical composition of this disclosure comprises an effective amount of a therapeutic agent, as disclosed herein, combined with a

pharmaceutically acceptable carrier. "Pharmaceutically acceptable," as used herein, includes any carrier which does not interfere with the effectiveness of the biological activity of the active ingredients and/or that is not toxic to the patient to whom it is administered. Non limiting examples of suitable pharmaceutical carriers include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents and sterile solutions. Additional non-limiting examples of pharmaceutically compatible carriers can include gels, bioadsorbable matrix materials, implantation elements containing the immunotherapeutic agents or any other suitable vehicle, delivery or dispensing means or material. Such carriers are formulated, for example, by conventional methods and

administered to the subject at an effective amount.

[0338] In some embodiments, the pharmaceutical composition is a formulation comprising an immunotherapy agent ( e.g ., an immune check point inhibitor, regulator, or activator) and a buffering agent. In some embodiments, the immunotherapy agent is present at a concentration of about 10 to about 50 mg/mL, about 15 to about 50 mg/mL, about 20 to about 45 mg/mL, about 25 to about 40 mg/mL, about 30 to about 35 mg/mL, about 25 to about 35 mg/mL, or about 30 to about 40 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 33.3 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, or about 50 mg/mL. In some embodiments, the formulation comprises a buffering agent comprising histidine (e.g., a histidine buffer). In certain embodiments, the buffering agent (e.g, histidine buffer) is present at a concentration of about 1 mM to about 20 mM, about 2 mM to about 15 mM, about 3 mM to about 10 mM, about 4 mM to about 9 mM, about 5 mM to about 8 mM, or about 6 mM to about 7 mM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 6.7 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM. In some embodiments, the buffering agent (e.g, histidine buffer) is present at a concentration of about 6 mM to about 7 mM, about 6.7 mM. In other embodiments, the buffering agent ( e.g ., a histidine buffer) has a pH of about 4 to about 7, about 5 to about 6, about 5.5, or about 6.

[0339] In some embodiments, the formulation further comprises a carbohydrate. In certain embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (e.g., sucrose) is present at a concentration of about 50 mM to about 150 mM, about 25 mM to about 150 mM, about 50 mM to about 100 mM, about 60 mM to about 90 mM, about 70 mM to about 80 mM, or about 70 mM to about 75 mM, about 25 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, or about 150 mM.

[0340] In some embodiments, the formulation further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant or polysorbate 20) is present at a concentration of about 0.005 % to about 0.025% (w/w), about 0.0075% to about 0.02% or about 0.01 % to 0.015% (w/w), about 0.005%, about 0.0075%, about 0.01%, about 0.013%, about 0.015%, or about 0.02% (w/w). In certain embodiments, the formulation is a reconstituted formulation. For example, a reconstituted formulation is prepared, in some instances, by dissolving a lyophilized formulation in a diluent such that the

immunotherapy agent is dispersed in the reconstituted formulation. In some embodiments, the lyophilized formulation is reconstituted with about 0.5 mL to about 2 mL, such as about 1 mL, of water or buffer for injection. In certain embodiments, the lyophilized formulation is reconstituted with 1 mL of water for injection at a clinical site.

Combination therapies

[0341] In certain embodiments, the methods of this disclosure comprise administering a therapeutic agent as disclosed herein, followed by, and preceded by or in combination with one or more further therapy. Examples of the further therapy can include, but are not limited to, chemotherapy, radiation, an anti-cancer agent, or any combinations thereof. The further therapy can be administered concurrently or sequentially with respect to administration of the immunotherapy. In certain embodiments, the methods of this disclosure comprise

administering an immunotherapy as disclosed herein, followed by, preceded by, or in combination with one or more anti-cancer agents or cancer therapies. Anti -cancer agents include, but are not limited to, chemotherapeutic agents, radiotherapeutic agents, cytokines, immune checkpoint inhibitors, anti-angiogenic agents, apoptosis-inducing agents, anti-cancer antibodies and/or anti-cyclin-dependent kinase agents. In certain embodiments, the cancer therapies include chemotherapy, biological therapy, radiotherapy, immunotherapy, cell therapy, hormone therapy, anti-vascular therapy, cryotherapy, toxin therapy and/or surgery or combinations thereof. In certain embodiments, the methods of this disclosure include administering an immunotherapy, as disclosed herein, followed by, preceded by or in combination with one or more further immunomodulatory agents. An immunomodulatory agent includes, in some examples, any compound, molecule or substance capable of suppressing antiviral immunity associated with a tumor or cancer. Non-limiting examples of the further immunomodulatory agents include anti-CD33 antibody or variable region thereof, an anti-CDl lb antibody or variable region thereof, a COX2 inhibitor, e.g ., celecoxib, cytokines, such as IL-12, GM-CSF, IL-2, IFN3 and IFNy, and chemokines, such as MIP-1, MCP-1 and IL-8.

[0342] In certain examples, where the further therapy is cell therapy, exemplary cell therapies include without limitation immune effector cell therapy, chimeric antigen receptor T-cell (CAR- T) therapy, natural killer cell therapy and chimeric antigen receptor natural killer (NK) cell therapy. Either NK cells, or CAR-NK cells, or a combination of both NK cells and CAR-NK cells can be used in combination with the methods disclosed herein. In some embodiments, the NK cells and CAR-NK cells are derived from human induced pluripotent stem cells (iPSC), umbilical cord blood, or a cell line. In some embodiments, the NK cells and CAR-NK cells comprise a cytokine receptor and a suicide gene. In some embodiments, the NK cells and CAR- NK cells are characterized by the presence of CD56 and the absence of CD3 surface markers. In some embodiments, the NK cells and CAR-NK cells target tumor cells (including solid tumors) and/or cells harboring viruses. In some embodiments, the NK cells and CAR-NK cells are administered in combination with an inhibitor of hyaluronan. In some embodiments, the NK cells and CAR-NK cells are administered in combination with an anti-PD-Ll therapy.

[0343] In certain examples, where the further therapy is radiation exemplary doses are 5,000 Rads (50 Gy) to 100,000 Rads (1000 Gy), or 50,000 Rads (500 Gy), or other appropriate doses within the recited ranges. Alternatively, the radiation dose are about 30 to 60 Gy, about 40 to about 50 Gy, about 40 to 48 Gy, or about 44 Gy, or other appropriate doses within the recited ranges, with the dose determined, example, by means of a dosimetry study as described above. “Gy” as used herein can refer to a unit for a specific absorbed dose of radiation equal to 100 Rads. Gy is the abbreviation for“Gray.”

[0344] In certain examples, where the further therapy is chemotherapy, exemplary

chemotherapeutic agents include without limitation alkylating agents (e.g, nitrogen mustard derivatives, ethylenimines, alkyl sulfonates, hydrazines and triazines, nitrosureas, and metal salts), plant alkaloids (e.g, vinca alkaloids, taxanes, podophyllotoxins, and camptothecan analogs), antitumor antibiotics (e.g, anthracyclines, chromomycins, and the like), antimetabolites (e.g, folic acid antagonists, pyrimidine antagonists, purine antagonists, and adenosine deaminase inhibitors), topoisomerase I inhibitors, topoisomerase II inhibitors, and miscellaneous

antineoplastics ( e.g ., ribonucleotide reductase inhibitors, adrenocortical steroid inhibitors, enzymes, anti microtubule agents, and retinoids). Exemplary chemotherapeutic agents can include, without limitation, anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine

(Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine

(Navelbine®), Ibrutinib, idelalisib, and brentuximab vedotin.

[0345] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desm ethyl dopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®);

Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC -Dome®); Altretamine (also known as

hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and

mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®,

Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1 (Treanda®).

[0346] Exemplary anthracyclines can include, without limitation, e.g ., doxorubicin

(Adriamycin® and Rubex®); bleomycin (Lenoxane®); daunorubicin (dauorubicin

hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine®); daunorubicin liposomal (daunorubicin citrate liposome, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin.

[0347] Exemplary vinca alkaloids include, but are not limited to, vinorelbine tartrate

(Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)); vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®).

[0348] Exemplary proteosome inhibitors can, but are not limited to, bortezomib (Velcade®); carfilzomib (PX- 171 -007, (S)-4-Methyl-N— ((S)- 1 -(((S)-4-m ethyl- 1 -((R)-2-methyloxiran-2-yl)- l-oxopentan-2-yl)amino)-l -oxo-3 -phenylpropan-2-yl)-2-((S)-2-(2-morpholinoac etamido)-4- phenylbutanamido)-pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708);

delanzomib (CEP-18770); and 0-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-0-methyl - N-[(lS)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-l-(phenylmethyl)e thyl]-L-serinamide (ONX-0912).

Model of NEPC

[0349] Another aspect described herein is a model ofNEPC comprising a transgenic animal with a transgene comprising a mutation of LAMTOR2 S30 site to alanine and genetic deletion of PTEN in the prostate epithelia. In some embodiments, the transgenic animal overexpresses NEPC biomarkers. In some embodiments, the transgenic animal overexpresses NEPC biomarkers in stroma of tumors of the transgenic animal. In some embodiments, the transgenic animal is produced by introducing, into an organism chosen from the group consisting of an animal cell and an animal embryo, an agent that specifically binds to a chromosomal target site of the cell and causes a double-stranded DNA break to induce a mutation of LAMTOR2 S30 site to alanine, with the agent being chosen from the group consisting of a TALEN, a zinc finger nuclease, Cas9/CRISPR and a recombinase fusion protein. In some embodiments, the transgenic animal comprises a mammal. In some embodiments, the transgenic animal comprises a mouse. In some embodiments, the transgenic animal comprises a rat. In some embodiments, the transgenic animal comprises a monkey. In some embodiments, the quantity of cells comprises an organoid.

[0350] Another aspect described herein is a model of NEPC comprising a transgenic animal with a transgene comprising a genetic modification that eliminates expression of PTEN and PKCl/i in the prostate epithelia. In some embodiments, the transgenic animal overexpresses NEPC biomarkers. In some embodiments, the transgenic animal overexpresses NEPC biomarkers in stroma of tumors of the transgenic animal. In some embodiments, the transgenic animal is produced by introducing, into an organism chosen from the group consisting of an animal cell and an animal embryo, an agent that specifically binds to a chromosomal target site of the cell and causes a double-stranded DNA break to eliminate expression of PTEN and PKCl/i, with the agent being chosen from the group consisting of a TALEN, a zinc finger nuclease, Cas9/CRISPR and a recombinase fusion protein. In some embodiments, the transgenic animal comprises a mammal. In some embodiments, the transgenic animal comprises a mouse. In some

embodiments, the transgenic animal comprises a rat. In some embodiments, the transgenic animal comprises a monkey. In some embodiments, the quantity of cells comprises an organoid.

EXAMPLES

[0351] The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.

Example 1 : PKCA/i is Downregulated in NEPC

[0352] Bioinformatics analysis of 60 PCa datasets revealed that while PRKCI expression was upregulated in primary tumors compared to normal tissue, it was downregulated in metastases (Figure 1A). In agreement with the downregulation of PKCl/i in aggressive disease, a molecular concept map analysis using signatures of PRKCI- correlated or /-WAT 7-anti -correlated genes derived from the MSKCC 2010 PCa dataset, demonstrated a negative association between PRKCI- correlated genes and metastasis, advanced cancer stage, and poor clinical outcome

(Figure IB). Patients with low levels of PRKCI expression had much lower relapse-free survival than patients with high PRKCI expression (Figure 1C). These results suggest that PKCl/i plays an unanticipated role as a tumor suppressor in late-stage PCa. To assess whether the loss of PKCl/i could be attributed to a defined molecular subset, a cohort of metastatic CRPC tumors was queried. Patients with low PKCl/i expression were significantly exclusive from the group with activating alterations in the AR gene (Figure 8A). Correlation analysis showed that low PKCl/i expression was associated with diminished AR activity (Figure 8B). When evaluating datasets of NEPC, it was found that PRKCI expression was significantly downregulated in NEPC compared to prostate adenocarcinoma CRPC samples (Figures ID and IE). No genomic amplifications or deletions of PRKCI were found in NEPC samples (Figure 8C). Molecular classification of primary and metastatic PCa samples revealed that PKCl/i downregulation was associated with the NEPC phenotype, independently of being primary or metastatic (Figure IE). PKCl/i expression was found highly correlated with genes that are differentially expressed in NEPC (Figure IF). These included the negative correlation with NEPC markers such as SYP, EN02 , NCAM1 , and CHGA , and the positive correlation with the AR downstream target KLK3 (PSA), as well as the NEPC repressor REST (Figure 1G). Reduced protein levels of PKCl/i were observed in a cohort of hormone naive NEPC with a de novo presentation, as compared to primary adenocarcinomas with high Gleason score (Figure 1H). PKCl/i expression was severely decreased in NCAM1 -positive prostate tumor areas, as well as in liver and lung NEPC metastases in TRAMP mice (Figure 8D). Analysis of gene expression data from the NEPC mouse model of prostate-specific simultaneous deletion of Pten and Rbl, or Pten, Rbl , and Trp53 showed reduced Prkci expression in NEPC tumors (Figure 8E). Consistently, PKCl/i protein levels were decreased in two different human NEPC cells lines (NE-1-3 and H660)

(Figure 11). These results suggest that NEPC tumors display low levels of PKCl/i expression.

[0353] To test whether PKCl/i loss could occur in therapy-related NEPC differentiation, enzalutamide-resistant LNCaP (LNCaP-ER) cells were generated. LNCaP-ER cells had increased levels of NEPC markers CD44 and NCAMl (Figure 1J). qPCR analysis of FACS-sorted CD44 ^h ' ^8h and NCAM 1 ^h ' ^8h cell populations from LNCaP-ER cultures showed additional hallmarks of NEPC concomitant with reduced PKCO/L mRNA and protein levels (Figure IK). Analysis of a tumor sample from a treated patient with high-burden disease, containing mixed prostate adenocarcinoma with extensive areas of NEPC differentiation, demonstrated a significant loss of PKCl/i expression in the NEPC areas as compared to the adenocarcinoma foci (Figure 1L). Interrogation of a dataset from a patient progressing on ADT comparing before and after enzalutamide treatment showed lower PRKCI mRNA levels in metastasis after treatment, which correlated with markers of NEPC differentiation and less AR activity (Figure 1M). These data support the notion that PKCl/i is reduced both in de novo NEPC and during treatment-related NEPC differentiation.

Example 2: Prostate-Specific Deletion of PTEN and PKCA/i Promotes Basal/NEPC

Tumorigenesis In Vivo

[0354] The Pten ^f/f -PbCre4 ⁺ mouse line (PTEN KO) in which Pten is specifically deleted in the prostate epithelium was crossed with Prkci ^f/f mice to generate Pten ^f/f -Prkci ^f/f -PbCre4 ⁺ mice (referred to as DKO). DKO mice had a much shorter lifespan than PTEN KO mice with a median overall survival of 180 days (Figure 2A). DKO prostates had enlarged dorsolateral and ventral prostate lobes, while age-matched PTEN KO mice only showed mild prostate enlargement

(Figure 2B). Histopathology of prostate sections revealed that tumor lesions from the DKO mice included more advanced prostate intraepithelial neoplasias (PIN) and increased incidence of carcinoma, with comedo-type necrosis and areas of invasion into the adjacent stroma (Figure 2C). DKO prostates showed increased stromal reaction and fibrosis, as determined by Masson’s trichrome and SMA staining (Figures 2D and 9A). DKO tumors displayed a marked increase in Ki67 ⁺ cells per gland, with proliferative cells mostly accumulated in the outer regions where basal cells are usually located (Figures 2E and 2F). DKO prostates showed higher abundance of TP63 ⁺ cells that overlapped with focal areas of high Ki67 staining (Figures 2E and 2F).

Approximately two thirds of the examined DKO prostates presented prostatic urothelial carcinomas (Figures 2C and 2G). These results suggested that PKCl/i loss in a PTEN KO background promoted an increase in highly proliferative basal-like cells. Consistently, DKO PIN showed increased cytokeratin 5 (CK5), decreased cytokeratin 8 (CK8) and lower nuclear AR staining (Figures 2H and 9B), which is in keeping with the emergence of basal cell identity and the loss of luminal features. More advanced tumor areas, including prostatic urothelial carcinomas, showed marked CK5 upregulation with high Ki67 ⁺ and TP63 staining, loss of nuclear AR, and areas positive for the NE marker chromogranin A (CHGA; Figure 21). FACS analysis showed an increase in NCAM1 staining in DKO basal cells (Figure 2J).

[0355] DKO-derived prostate organoids had increased growth (Figure 2K), and expression of NEPC and basal markers (Figure 2L). Similar results were obtained in PTEN KO organoids upon lentiviral shRNA of PKCl/i (Figure 9C). DKO-derived prostate organoids were resistant to enzalutamide treatment as compared to PTEN KO organoids that showed a significant reduction in size upon treatment (Figure 2M). These results demonstrate that the concomitant deletion of PTEN and PKCl/i in the mouse prostate epithelium accelerates PCa progression and leads to the emergence of highly proliferative lesions with loss of luminal cell identity and gain of basal and NEPC features.

Example 3 : Loss of PKCA/i is Sufficient to Promote NEPC Differentiation at a Cellular Level

[0356] Lentiviral-mediated shRNA of PKCl/i in these cells was sufficient to induce NEPC and basal cell markers concomitant with the downregulation of AR and of AR targets (Figures 3A and 3B). Similar gene expression changes were observed upon CRISPR/Cas9-mediated inactivation of PKCl/i (sgPKCl/i) in C42B cells (Figures 3C and 3D). Re-expression of PKCl/i into sgPKCl/i -cells (sg PKCl/i-R) restored these markers to the levels of control cells (sgC) (Figures 3C and 3D). PKCl/i was stably knocked down (KD) in the immortalized non- transformed prostate epithelial cell line (PrEC). GSEA of genes differentially expressed in shPKCl/i cells showed similar transcriptomic profiles to human NEPC (Figures 3E and 10A). NEPC is also characterized by a remarkable increase in cellular proliferation, which is mediated by the activation of E2F (Figure 10B, left panel). Interestingly, PRKCI expression was negatively correlated with the hallmark“E2F Targets”, and positively correlated with“Androgen Response” gene set (Figure 10B, right panel. LNCaP shPKCl/i cells showed increased in vitro proliferation in androgen-deficient conditions and were able to grow even in the presence of enzalutamide treatment whereas shNT LNCaP cells were not (Figure 3F). LNCaP shPKCl/i cells showed increased expression of cell cycle regulatory genes and increased colony formation activity (Figures 3G and IOC). KD of PKCl/i in PC3 and DU145, two androgen-independent cell lines, enhanced proliferation concomitant with higher expression of NEPC markers (Figures 10D-10G). Conversely, overexpression of PKCl/i in PC3 or DU145 strongly decreased cell proliferation, colony formation and SYP expression (Figures 3H and 10H-10J). sgPKCl/i C42B cells showed higher proliferation under androgen-deficient condition and had increased basal levels of E2F1 (Figures 31 and 3J). sgPKCl/i cells displayed also a higher proliferative capacity in vivo in tumor xenografts and were less sensitive to enzalutamide treatment than sgC cells (Figures 3K and 10K). Tumor growth was rescued upon re-expression of PKCl/i in sg PKCl/i cells (Figure 3K). These results demonstrate that the loss of PKCl/i is sufficient to promote NEPC differentiation in a cell-autonomous manner in vitro and in vivo. Example 4: PKC2/i Regulates mTORCl Activity through LAMTOR2 Phosphorylation

[0357] Transcriptomic profiling of shNT and shPKCl/i PrEC cells was carried out as well as of sgC, sgPKCl/i, and sgPKCl/i-R cells. GSEA revealed“mTORCl Signaling”,“MYC targets” and cell -cycle related signatures to be upregulated in PKCl/i deficiency conditions, which was reverted in sgPKCl/i-R cells (Figures 4A and 4B). Investigate Gene Set analysis (Broad Institute) with genes that were differentially expressed in sg PKCl/i as compared to sgC and rescued in sg PKCl/i-R identified gene sets corresponding to mTORCl and AR signaling as the most upregulated and downregulated, respectively (Figures 11A and 11B). mTORCl was activated in sgPKCl/i cells as determined by western-blot of three downstream effectors, p4EBPl, pS6K and cMYC (Figure 4C). The kinase activity of PKCl/i was required to inhibit mTORCl since the WT form of PKCl/i but not its kinase inactive mutant (K274W), was able to rescue mTORCl activation in sg PKCl/i cells (Figure 4C). Increased activation of mTORCl was also detected in PIN lesions of DKO mice, as determined by pS6 (Ser240/244) staining (Figures 4D and 4E). mTORCl inhibition by rapamycin treatment in sgPKCl/i cells restored the levels of NEPC and basal markers to control levels (Figures 4F and 4G). GSEA revealed that inhibition of mTORCl with Torinl in LNCaP cells that had been starved of androgens for 2 days significantly correlated with a decrease in genes overexpressed in NEPC (Figure 4H).

These results demonstrate that the activation of mTORCl upon PKCl/i deficiency is central to NEPC differentiation.

[0358] To dissect the regulatory mechanism between PKCl/i and mTORCl, interactors of PKCl/i were identified using the proximity-dependent biotin method (BioID2) in LNCaP cells

(Figure 11C). p62/SQSTMl, a bona fide PKCl/i interactor, was identified in this screening, which validated the approach (Figure 41). Among the proteins found exclusively in PKCl/i-

BioID2 samples, LAMTOR2 stood out as a potential link between PKCl/i and mTORC1

(Figure 41). LAMTOR2 is part of the Ragulator, which is a pentameric scaffold complex that regulates mTORCl at the lysosome membrane. Other components of the endosomal/lysosomal system, including LAMP2, KIF2C/B and V-ATPases were also found as PKCl/i interactors

(Figure 41). LAMTOR2 colocalized and co-immunoprecipitated with endogenous PKCl/i

(Figures 4J and 4K). PKCl/i was able to directly phosphorylate LAMTOR2 in an in vitro kinase assay (Figure 4L). Serine 30 in LAMTOR2 was predicted as the unique phosphorylation site by PKCl/i using Scansite 4.0 and is highly conserved across species (Figure 11D). Mutation of LAMTOR2 S30 site to alanine significantly reduced PKCl/i phosphorylation (Figure 4M).

Analysis of the crystal structure of the Ragulator complex revealed that LAMTOR2 associates with the RagA/B and RagC/D GTPases, which are important to activate mTORCl. Serine 30 is located at the interface of LAMTOR2 with the Rag GTPases (Figure HE), which could impact complex formation, recruitment to lysosomes and mTORCl activation. In fact, we detected enriched expression of LAMTOR2, and the other components of the RagulatonRag complex, in lysosomal membranes of sgPKCl/i cells (Figure 11F). Expression of the LAMTOR2 S30A mutant in C42B cells was sufficient to increase mTORCl activity and NEPC markers (Figure 4N). PKCl/i deficient cells revealed a strikingly different lysosomal distribution compared to sgC cells, which included perinuclear aggregation of lysosomes, and increased amount of mTOR and RagC proximal to the nucleus, where Rheb, a key activator of mTORCl is enriched (Figure 40)

[0359] Treatment with CilioD, a dynein inhibitor that blocks the retrograde transport system, reduced mTORCl activity of sgPKCl/i cells to control levels (Figure 4P). The expression of LAMTOR2 S30A mutant mimicked the lysosomal phenotype of sgPKCl/i cells, and promoted the perinuclear aggregation of lysosomes (Figure 4Q). Consistent with increased mTORCl activation, the interaction of mTOR with LAMTOR2 in sgPKCl/i cells was stronger than in sgC cells (Figure 4R). Likewise, the LAMTOR2 S30A mutant displayed enhanced affinity for mTOR than LAMTOR2 WT (Figure 4S). These data support a model whereby PKCl/i inhibits mTORCl activation by forcing the dispersion of lysosomes and impairing its interaction with LAMTOR2 through phosphorylation of the S30 (Figure 4T).

Example 5: Loss ofPKCl/i Increases Serine Metabolism through the mTORCl /ATF4/PHGDH Axis

[0360] Pathway analysis of gene expression data generated in a C42B cell line model was carried out. This analysis revealed ATF4 as the main activated upstream regulator in PKCl/i-deficient cells (Figure 5A). Consequently, many targets of this transcription factor, including ATF4 itself, appeared upregulated in sgPKCl/icells (Figure 12A). Increased ATF4 was confirmed by immunoblotting (Figure 5B). siRNA-mediated KD of PKCl/i in LNCaP cells promoted upregulation of ATF4 (Figure 12B), and tumor lesions in the DKO mice showed increased nuclear ATF4 staining (Figure 5C). Upregulation of ATF4 in PKCl/i-deficient cells was reduced by inhibition of mTORCl with rapamycin or siRNA-mediated KD of Raptor, while no changes in any of the three branches of the UPR were observed (Figures 5B and 12C-12E). ATF4 KD by shRNA in sgPKCl/i cells resulted in reduced levels of NEPC and basal markers (Figures 5D and 5E), as well as impaired cell proliferation (Figure 5F). To delineate which subset of ATF4 targets were upregulated upon PKCl/i loss, the ATF4 cistrome was compared with genes upregulated in sgPKCl/i cells and unbiased pathway analysis was performed. Serine and glycine biosynthesis appeared as the most significantly upregulated signature (Figure 12F). GSEA revealed significant enrichment in sgPKCl/i of a recently generated SGOCP gene signature, as compared to sgC and sgPKCl/i-R cells (Figure 5G). This included key genes of the pathway such as PHGDH , MTHFD2 , and PSAT1 (Figure 5G). Several genes of the SGOCP were found to be upregulated in LNCaP cells transfected with an siRNA PKCl/i (Figure 12G), as well as in shPKCl/i PrEC cells (Figure 12H). ATF4, PHGDH and NEPC markers were rescued by the WT form of PKCl/i but not by its kinase-dead mutant (Figure 5H). Both shRNA- mediated KD of ATF4 and rapamycin treatment inhibited the expression of the SGOCP genes (Figures 51 and 5J). Ectopic expression of ATF4 in LNCaP cells promoted the induction of SGOCP genes, concomitant with an increase in NEPC and basal markers (Figures 5K and 5L). E2F1 upregulation was reduced upon mTORCl and cMYC inhibition but was not altered by changes in ATF4 levels (Figures 5I-5L and 121). shRNA-mediated KD of PHGDH reduced NEPC and basal markers (Figures 5M and 5N), and partially inhibited the growth advantage of sgPKCl/i cells (Figure 50).

[0361] Whether transcriptional changes driven by the ATF4/SGOCP axis translated into a metabolic phenotype in sgPKCl/i cells was investigated. Analysis of metabolite abundances revealed that sgPKCl/i cells displayed increased intracellular levels of glycine, but not serine (Figure 12 J). Since serine conversion to glycine serves to donate 1C units to the One Carbon Pool, these results suggest an accumulation of glycine downstream of increased serine synthesis. sgPKCl/i cells had lower lactate/glucose ratios than control cells, despite increased cellular proliferation, which indicated a difference in glucose utilization, likely by the diversion of carbons to the SGOCP (Figure 12K). Tracing analysis of uniformly labeled [U-13C6]Glucose showed serine and glycine as the top two metabolites with increased labeling (Figures 5P, 5Q and 12L). sgPKCl/i cells displayed higher glycine efflux despite increased glycine

accumulation, while no changes in serine efflux were observed (Figure 12M). Tracing of [a- ¹⁵ N] Glutamine, which donates IN via glutamate during the step catalyzed by PSAT1, showed increased labeling in serine and glycine (Figure 5R). These results demonstrate that the loss of PKCl/i activates mTORCl to drive an ATF4 -dependent gene transcription program that promotes NEPC differentiation and results in the metabolic reprogramming of PCa cells to increase the flux through the SGOCP. Example 6: Loss ofPKCAJi Increases DNA Methylation to Promote NEPC Differentiation

[0362] Serine metabolism fuels the methionine salvage pathway to produce SAM for DNA methylation. Since epigenetic regulation has been recently recognized as a prognostic value to distinguish indolent from aggressive forms of prostate cancer, the hypothesis that increased SGOCP could affect the lineage specificity of NEPC through epigenetic modulation was tested. First, whether increased SGOCP in PKCl/i deficient cells could promote incorporation of SGOCP-derived carbon units into genomic DNA was assessed. Indeed, PKCl/i had increased methyl-cytosine labeling from [methyl- 13 CJMethionine, a measure of 1C units donated from SAM pools (Figure 14A). 5mC dot-blot analysis of whole genomic DNA extracts showed increased DNA methylation in sgPKCl/i cells, which was confirmed by MS data of total MeCyt to Cytosine ratios (Figures 7A and 14B). The intracellular levels of SAM were upregulated in sgPKCl/i cells, which were rescued by the KD of PHGDH that also inhibited global genomic methylation levels (Figures 7A and 7B). Similarly, KD of ATF4, or inhibition of mTORCl with rapamycin, reduced SAM to control levels in sgPKCl/i cells (Figures 14C and 14D).

[0363] The methylome of sgPKCl/i and sgC cells was characterized by Methylated DNA Immunoprecipitation followed by NGS (Medip-seq). PKCl/i loss promoted an increase in genome wide methylation, as detected by enhanced median region methylation scores (Figure 7C), which included differential methylation in regions within and around gene bodies (Figure 14E). Differentially methylated regions (DMR) in sgPKCl/i cells (DMR-sgPKCl/i) had a significant overlap with their differentially expressed genes (Figures 7D and 7E). These results demonstrate that the alterations in DNA methylation in sgPKCl/i cells are correlated with transcriptional changes. Transcription factor enrichment analysis of clustered regions was then performed based on methylation profiles around genes differentially expressed between sgPKCl/i and sgC cells. Upregulated genes clustered by methylation profiles showed an enrichment of binding motifs for Pax5, Nr5a2 and Oct4-Sox2-Tcf-Nanog transcription factors, which have been previously involved in embryonic morphogenesis, neural development and maintenance of stem cell traits (Figure 14F). On the other hand, downregulated genes clustered by methylation profiles included a subset that showed an enrichment for Androgen Response Element (ARE), which suggested that DNA methylation could contribute to the loss of AR activity (Figure 14G). In fact, the KD of PHGDH rescued the expression of hypermethyl ated and downregulated genes in sgPKCl/i cells, including the AR-dependent gene AD AMTS l and the negative regulator of cell cycle CDKN1A (p21) (Figure 7F). These observations are of clinical relevance since DMR sgPKCl/i regions contained a statistically significant overlap with CpG areas found hypermethyl ated in NEPC patients, as well as those found hypermethylated in highly aggressive PCa (Figure 7G). Gene Ontology (GO) pathway analysis of DMR-sgPKCl/i- associated genes, hypermethylated NEPC CpGs, and DMR of highly aggressive PCa, showed a clear enrichment in development-related gene signatures, including“embryonic morphogenesis”, “pattern specification”, and“cell morphogenesis involved in neuron differentiation” processes (Figure 14H). These data indicate that the DNA methylation changes observed upon PKCl/i deficiency impact the expression of genes central to the control of cell-type specification, which are similar to those observed during NEPC differentiation.

Example 7: DNMT Inhibition Blocks NEPC Differentiation and Tumor Growth

[0364] To investigate the therapeutic potential of the inhibition of DNMT activity in NEPC, sgPKCl/i cells were treated with decitabine (Aza), a pharmacological inhibitor of DNMT, or with cycloleucine (Cyclo), which blocks the last enzyme in the production of SAM (MAT), and therefore the metabolic flux that supplies methyl donors for the DNMT reaction (Figure 141). Aza treatment severely reduced NEPC and basal markers in sgPKCl/i cells to levels like those in sgC cells (Figures 7H and 71). Similarly, Cyclo reduced the expression of basal and NEPC markers in sgPKCl/i cells (Figures 7J and 7K). Both drugs had a potent anti-proliferative effect on sgPKCl/i C42B cells (Figure 7L). Aza treatment was effective in blocking the proliferative advantage of DKO organoids and reduced the expression of Ncaml to levels of PTEN KO organoids (Figures 7M and 7N). Aza treatment of sgPKCl/i-derived xenografts inhibited both the growth of already stablished tumors and the levels of 5mC and NCAMl to those of vehicle- treated samples (Figures 70 and 7P). Importantly, KD of PHGDH also completely inhibited the growth advantage of sgPKCl/i tumors (Figure 70). These results support a model whereby the metabolic reprogramming orchestrated by PKCl/i deficiency through the

mTORCl/ATF4/PHGDH axis creates a vulnerability in NEPC that can be exploited

therapeutically by targeting the SGOCP and DNA methylation.

Example 8: Increased levels of hyaluronan and CD44 expression in prostate tumors

[0365] Histopathology of prostate section of DKO mice revealed that the stroma of DKO prostate tumors displayed increased level of hyaluronan in both prostate intraepithelial neoplasias (PIN) and carcinoma areas as compared to the stroma of PTEN KO prostates (Figure 16A). In addition, DKO prostate tumors showed increased expression of CD44, a hyaluronan receptor, which is also a marker for cancer stem cells and neuroendocrine tumors (Figure 16B). The increased level of HA in the stroma could further support tumor growth through the interaction with its receptor CD44 to fuel neuroendocrine prostate tumors.

Materials and Methods

Animal Models

[0366] C57BL/6 background Pten ^f/f -PbCre 4 ⁺ mice were generated by breeding Pten ^f/f -PbCre 4 females with Pten ^f/wt -PbCre4 ⁺ males. C57BL/6 background Pten ^f/f -Prkci ^f/f -PbCre 4 ⁺ mice were obtained from crossing Pten ^f/f -Prkci ^f/f -PbCre4 females with Pten ^f/f -Prkci ^f/f -PbCre4 ⁺ males. Prkci ^f/f mice have been previously described in. For the xenograft experiments, NSG mice of 2 months of age were used. NSG mice were purchased from the animal core at SBP Medical Discovery Institute. All mice were born and maintained under pathogen-free conditions. Animal handling and experimental procedures conformed to institutional guidelines and were approved by the Institutional Animal Care and Use Committee at SBP Medical Discovery Institute. All genotyping was done by PCR. The WD (D12079B; OpenSource Diets) was available ad libitum. Experimental mice were all males. NSG mice were randomized between litters to prevent a bias towards age. Sex- and age-matched animals were allocated from each genotype into experimental groups. An identification code was assigned to each animal and the investigators were not blinded to group allocation at the time of data collection and analysis. For prostate organoid isolation, dorsolateral and ventral lobes for each mouse genotype were used and established as described under prostate organoid culture. For mouse xenografts, sgC or sgPKCl/i C42B cells were trypsinized, washed two times in cold PBS, aliquoted to 250K per dose in a 50 mΐ volume and injected subcutaneously into both flanks of male NSG mice. Measurements were done weekly using a caliper. Daily gavage treatment with lOmg/kg enzalutamide or Vehicle (using a formulation of 1% carboxymethyl cellulose, 0.1% Tween-80, 5% DMSO) was initiated on the day of injection. Treatment by IP injection of lmg/kg Aza in PBS or vehicle was initiated when tumors reached an average size of 250 mm ³ and administered three consecutive days weekly. Human Samples

[0367] FFPE tissue samples from male PCa patients were obtained from Scripps Clinic and Complejo Hospitalario Universitario de Albacete (CHUA) (Albacete, Spain). Written informed consent was obtained from all patients with the protocol approved by the Ethics Committee of CHUA and Scripps Green Hospital in accordance with the ethical guidelines for epidemiological research, as well as the principles expressed in the Declaration of Helsinki. Samples were de- identified in terms of all the covariate relevant details such as age, sex, and past history, and were sent to SBP Medical Discovery Institute and used for histological analyses. Informed consent was obtained from all participants. The study was approved by the IRB Committee of SBP Medical Discovery Institute.

Cell lines

[0368] HEK293T (sex: female), C42B (sex: male), LNCaP-FGC (sex: male), PC3 (sex: male), DU145 (sex: male) and Phoenix-GP (sex: female) were obtained directly from ATCC. PrEC cell line (sex: male) was purchased from LONZA. All cells were negative for mycoplasm.

Cell Culture Experiments

[0369] LNCaP and C42B cells were cultured in Rosewell Park Memorial Instiute 1640 (RPMI 1640, GIBCO). PC3, HEK293T, and DU145 were cultured in Dulbecco’s Modified Eagles Medium (DMEM). NE-1-3 and H-660 were cultured in RPMI1640 without phenol red (GIBCO). All base mediums were supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, and 100 U/mL penicillin and 100 pg/mL streptomycin, in an atmosphere of 95% air and 5% C02, except for NE-1-3 and H-660 that 5% Charcoal Stripped Serum (CSS) was used. Lentiviruses and retroviruses were prepared and used as previously described. The following treatments were applied as follows; rapamycin was used at 100 nM, cycloleucine was used at 2 mM with daily media change, azacytidine was used at 5 mM, and DHT was used at 10 nM. Androgen

Deprivation Therapy conditions consisted on RPMI1640 media without phenol red (GIBCO), 10% dialyzed FBS, Glutamax and 100 U/mL penicillin 100 and 100 pg/mL streptomycin.

Cell lysis , immunoprecipitation and western blotting

[0370] Cells for protein analysis were lysed in RIPA buffer (20 mM Tris-HCl, 37 mM NaCl, 2 mM EDTA, 1% Triton-X, 10% glycerol, 0.1% SDS, and 0.5% sodium deoxycholate, with phosphatase and protease inhibitors). For immunoprecipations, cells were lysed in s3 buffer (100 mM NaCl, 25 mM Tris, 1% Triton-X, 10% glycerol, with phosphatase and protease inhibitors) and immunoprecipitated with 25 pi of 50% slurry of protein Glutathione-Sepharose 4B beads (Bioworld). Immunoprecipitates were washed three times with lysis buffer, once with high salt (500 mM NaCl), and once more with lysis buffer. Cell extracts and immunoprecipitated proteins were denatured, subjected to SDS-PAGE, transferred to PVDF membranes (GE Healthcare), and immunoblotted with the specific antibodies as listed in STAR methods Reagents table.

SAM quantification assay

[0371] Quantification of intracellular SAM levels was performed according to manufacturer’s instructions (Bridge-It S-Adenosyl Methionine (SAM) Fluorescence Assay, 96-well microplate format, Mediomics). In brief, 5x104 cells were pelleted in PBS and resuspended in 30 Dl of Buffer CM and incubated at 24 °C for lhr, with occasional vortex. Samples were cleared by centrifugation at 4 °C 10,000 x g for 5 minutes and the supernatants were analyzed and quantified together with the SAM standard curve.

Gene Expression Analyses

[0372] Total RNA was extracted by using TRIzol reagent (Invitrogen), and purified by using RNA miniprep kit (OmnigenX, OR3220-2) following the manufacturer’s protocol. After quantification using a Nanodrop 1000 spectrophotometer (Thermo Scientific), 1 pg of RNA was reverse-transcribed using random primers and MultiScribe Reverse Transcriptase (Applied Biosystems). Gene expression was analyzed using the CFX96 Real Time PCR Detection System with SYBR Green Master Mix (BioRad). Primer sequences are listed in Table SI. The amplification parameters were set at 95 °C for 30 s, 58 °C for 30 s, and 72 °C for 30 s (40 cycles total). Gene expression values for each sample were normalized to the 18S rRNA or b-actin indistinctively. RNASeq studies were performed in the Genomics Core at SBP Medical

Discovery Institute. Briefly, total RNA was extracted from sgC, sgPKCl/i, and sgPKCl/i-R. PolyA RNA was isolated using the NEBNext® Poly(A) mRNA Magnetic Isolation Module and barcoded libraries were made using the NEBNext® UltraTM Directional RNA Library Prep Kit for Illumina® (NEB, Ipswich MA). Libraries were pooled and single end sequenced (1X75) on the Illumina NextSeq 500 using the High output V2 kit (Illumina Inc., San Diego CA).

Sequencing Fastq files were uploaded to BaseSpace and processed with RNAexpress App (Illumina) to obtain raw reads counts for each gene.

Bioinformatics analysis of gene expression

[0373] Microarray studies were performed in the Genomics and Microarray Laboratory at the Department of Environmental Health, University of Cincinnati Medical Center. Briefly, total RNA was extracted from 3 independent plates of PrEC siC and siPKCl/i and hybridized on Affymetrix mouse ST 1.0 microarrays. Scanning of the images and the first pass processing of probe-level fluorescence intensities was performed using the Microarray Suite 5.0 software (MAS 5.0; Affymterix, Santa Clara, CA). Gene expression tables (.get) used as input for GSEA were created by processing CEL files with ExpressionFileCreator module hosted at GenePattern (https://genepattern.broadinstitute.org) with RMA method, using quantile normalization and background correction. Gene matrix files generated with RNAexpress app (Illumina) were modified to comply with .get format and used as input file for Gene set enrichment analysis. GSEA was performed using GSEA v2.0.14 software

(http://www.broadinstitute.org/gsea/index.jsp) with 5000 gene-set permutations using the gene ranking metric T-test with Hallmark, C2, C3, C5 and C6 MSigDb collections as specified in each case. Heat-map representation of gene expression was generated using Morpheus (Broad Institute). Differentially expressed genes using Deseq2 with q-value<0.05 were considered to be significantly differentially expressed and uploaded to IPA (QIAGEN) to be analyzed using“Core Pathway Analysis”. Mutual exclusivity analysis of molecular alterations and PKCZ/i expression in human patients (Robinson 2015 dataset) was performed using cBioPortal

(http://www.cbioportal.org/) using samples with transcriptomic data (n = 118). Potential ATF4 targets in PCa (n = 3240 genes) were obtained from a comprehensive resource of predicted transcription factor (TF) targets and enhancer profiles in cancer, which integrates analysis of TCGA expression profiles and public ChIP-seq profiles (cistrome.org). 114 potential ATF4 targets were upregulated in sgPKCl/i cells compared to sgC. The list of 114 genes was used to perform unbiased pathway analysis on IPA.

Unsupervised clustering of patient samples

[0374] Gene expression data for GSE77930 and GSE59984 were accessed through GEO

(https://www.ncbi.nlm.nih.gov/geo/) and MSKCC PCa 2010 was directly downloaded from MSKCC. K-means (n=2) clustering was performed using gene expression values for the genes included in the previously published Integrated NEPC Signature (Beltran et al., 2016). The following genes were omitted in GSE77930 because lack of information: AR, ARHGAP8, C70RF76, KIAA0408, OPHN1 and PIEZO 1.

Medip-seq

[0375] Methylated DNA Immunoprecipitation was performed as follows. Total genomic DNA from samples was extracted using QIAamp DNA mini kit (QIAGEN) and eluted in DDW. 20 jtg of total genomic DNA was diluted in 50 jtl TE and sonicated using Covaris S2 with the following parameters (Duty 5%, Cycles/burst = 200, time=60s, 4 cycles using a microTUBE AFA Fiber Snap-Cap). Sonicated DNA was cleaned with Qiagen PCR clean UP (QIAGEN) and eluted in 30 jtl of EB. 2 jtg of sonicated genomic DNA was used to prepare libraries using NEBNext Ultra II DNA Library Prep kit (Illumina) following manufacturer’s instructions. Size-selected, end- repaired and adapter-ligated fragments (libraries) were denatured 10 min at 95C and immediately transferred to ice. 500 ng of library DNA were diluted in 500 jtl of ice-cold IP buffer (20mM Tris-Cl, pH 8, 2mM EDTA, 1% Triton-X, 150 mM NaCl) with the addition of 1 jtg of anti-5mC antibody (33D3, Diagenode) and incubated at 4 °C overnight. Same amount of library was kept aside for input sequencing and incorporated later to the Elution steps. IP pull down was performed with appropriate amount of Protein A Sepharose (SantaCruz) for 2 hr at 4 DC on orbital rotation. After Pull-down, Protein-A Sepharose beads were washed twice with IP Buffer, once with High Salt buffer (IP Buffer with 300 mM NaCl), twice with TE buffer and finally resuspended in 400 mΐ of Elution Buffer (25 mM Tris-Cl; pH 8.0, 10 mM EDTA, 0.5% SDS) with the addition of 10 mΐ of Proteinase K and samples were heated at 55C for 1 hr. After Elution, DNA was purified using PCR cleanup kit (QIAGEN) and eluted in 18 mΐ of EB. Library quality of IP 5mC outputs and inputs was analyzed with Bioanalyzer. DNA sequencing was done in a NextSeq 500 (Illumina).

Medip-seq data processing and analysis

[0376] Files were uploaded to usegalaxy.org server. After passing FASTQC analysis, raw

FASTQ sequence quality files were converted with FASTQ Groomer and aligned to human genome (hgl9) with BWA for Illumina with default parameters. Aligned SAM files were converted to BAM and sorted by chromosome position. Alignment statisitics was calculated using FlagStat. Peak Calling was performed using MACS2 peakcalling with the following parameters: Effective genome size=2451960000, Band width for picking regions to compute fragment size=300, Set lower mfold bound=5, Set upper mfold bound=50, Peak detection based on=q-value, Minimum FDR (q-value) cutoff for peak detection=0.01, Build

Model=create_model, When set, scale the small sample up to the bigger sample=False, Use fixed background lambda as local lambda for every peak region=False, When set use a custom scaling ratio of ChIP/control (e.g., calculated using NCIS) for linear scaling=1.0, The small nearby region in basepairs to calculate dynamic lambda=1000, The large nearby region in basepairs to calculate dynamic lambda= 10000, Composite broad regions=nobroad, How many duplicate tags at the exact same location are allowed=l. Bedgraph files from MACS2 output were converted to BigWig for Peak visualization. DMR were calculated using MACS2 bdgdiff using 5mC outputs and inputs for each sample with correction for sequencing depth and -g 60. Genomic Regions were annotated using EpiExplorer and NextBio using PileUp values as peak scores. Analysis of Overlap between bed files was performed using NextBio and the function Intersect at The Genomic Hyperbrowser as described in EpiExplorer documentation (epi explorer. mpi- inf.mpg.de). Methylation profile analysis was performed using ComputeMatrix and PlotHeatmap packages within Deeptools with default options. Genomic coordinates for human Refseq genes were downloaded from UCSC Table browser. Transcription factor enrichment analysis was performed with HOMER.

Isotopic Labeling

[0377] sgC and sgPKCl/i C42B cells were cultured in RPMI 1640 medium including 10 mM [U-13C6] glucose or 2 mM [A- ¹⁵ N]Glutamine, and 10% (v/v) dialyzed FBS for 24 and 48 hr prior to metabolite extraction. Labeling (corrected for natural abundance using in-house software) is depicted as isotopologue distributions or as labeled fraction of metabolites. Metabolite abundances were normalized to cell counts. Serine and glycine secretion rates are depicted as level of labeled secreted metabolite relative to integral of viable cells (IVC).

Gas Chromatography-Mass Spectrometry (GC-MS) Sample Preparation and Analysis

[0378] Cells were washed with saline solution and quenched with 0.5 mL -20 °C methanol. After adding 0.2 ml 4°C cold water, cells were collected in tubes containing 0.5 mL -20 °C chloroform. The extracts were vortexed for 10 min at 4°C and centrifuged at 16,000xg for 5 min at 4 °C. The upper aqueous phase was evaporated under vacuum at -4 °C. To determine extracellular metabolite levels, medium was centrifuged for 5 min at 300xg and 10 mΐ of supernatant was extracted using water/methanol/chloroform as described above. Derivatization for polar metabolites was performed using a Gerstel MPS with 15 pi of 2% (w/v) methoxyamine hydrochloride (Thermo Scientific) in pyridine (incubated for 60 min at 45 °C) and 15 mΐ N- tertbutyldimethylsilyl-Nmethyltrifluoroacetamide (MTBSTFA) with 1% tert- butyldimethylchlorosilane (Regis Technologies) (incubated further for 30 min at 45 °C). Polar derivatives were analyzed by GC-MS using a DB-35MS column (30 m x 0.25 i.d. x 0.25 mih) installed in an Agilent 7890A gas chromatograph (GC) interfaced with an Agilent 5975C mass spectrometer (MS) operating under electron impact ionization at 70 eV. The MS source was held at 230°C and the quadrupole at 150 °C and helium was used as carrier gas. For MTBSTFA derivatized samples, the GC oven was held at 100 °C for 1 min, increased to 300 °C at 10 °C/min, and held at 325 °C for 3 min.

Analysis of methyl cytosine

[0379] Cells were grown in amino acid-free RPMI 1640 supplemented with all 12C amino acids and [methyl- 13 C]Methionine at standard RPMI with 10% FBS and 2 mM glutamine

concentrations for 4 hr. Cells were rinsed with PBS, pellets collected by scraping and

centrifugation, and then snap frozen in liquid nitrogen. Cellular biomass was collected and hydrolyzed for GC/MS analysis. Pellets were extracted by addition of 500 jtL -80 °C methanol, 200 jtL water, and 500 jtL chloroform with subsequent pellet disruption in Restch Mixer Mill for 30 s at 30 Hz, vortexing for 10 s, and centrifugation at 20000 rpm for 10 min at 4 °C. Interfacial layer (containing nucleotide polymers) was isolated by discarding upper aqueous phase and lower organic phase from extraction and washing twice by addition of 500 jtL methanol, vortexing, and discarding supernatant after centrifugation at 20000 rpm for 10 min at 4°C.

Interfacial layer was dried ambiently overnight in fume hood. Nucleobases were isolated by acid hydrolysis for 2 hr at 80 °C with 2 M HC1 and subsequently dried under ambient air flow. Dried hydrolysate was resuspended in 500 jtL 90% methanol and 50 jtL redried for GC/MS analysis. Samples were derivatized with MTBSTFA and measured as described above. GC oven was held at 100 °C for 1 min after injection, increased to 255 °C at 3.5 °C/min, and finally increased to 320 °C at 15 °C/min and held for 3 min.

Quantification and statistical analysis

[0380] Statistical analyses for figures were performed using GraphPad Prism software (San Diego, CA). Data are presented as the mean ± SD unless otherwise specified. For qPCR experiments, Gaussian distribution was assumed and a Student’s t-test (two-tailed unpaired) was used to determine statistical significance. For human and mouse studies, significant differences between groups were determined using a Student’s t-test (two-tailed unpaired) when the data met the normal distribution tested by D’Agostino test. For statistical analysis of metabolite abundances and fraction labeling, significant differences were determined when both p values of sgPKCl/i vs sgC and sgPKCl/i vs sgPKCl/i-R comparisons were below p value<0.05 using Tukey’s multiple comparison test. For statistical analysis of radial profile distribution values, significance was determined by unadjusted multiple comparisons by t-test over 750 data points. All experiments were performed at least three independent times, unless otherwise noted. Gene expression correlation analyses were performed using Pearson’s correlation coefficients, with a two-tailed test. A log-rank (Mantel-Cox) test was used to evaluate statistical significance for the Kaplan-Meier survival plots. The significance level for statistical testing was set at p < 0.05. For animal xenograft studies, we used G*Power Data analysis to ensure adequate power to detect a pre-specified effect size. Specifically, based on preliminary qPCR data of E2F1 gene expression in sgC and sgPKCi C42B cells, as a surrogate for cell proliferation potential of these cells, we calculated sample size assuming power of 0.80 and 5% Type I error rate (alpha=0.05) with sampling ratio=l. No statistical method was used to predetermine any other sample sizes.

Histology and immunohistochemistry

[0381] Prostates were isolated, rinsed in ice-cold PBS, fixed in 10% neutral buffered formalin overnight at 4 °C, dehydrated, and embedded in paraffin. For CD44 staining, sections (5 pm) were deparaffmized, rehydrated, and then treated for antigen retrieval (Citrate, pH6) with heat. After blocking in Protein Block Serum-Free solutions (DAKO), tissues were incubated with primary antibody (anti-mouse CD44 (Bio-Rad, MCA4703)) overnight at 4 °C followed by incubation with biotinylated secondary antibody. Endogenous peroxidase was quenched in 3% H2O2 in water for 10 minutes at room temperature. Antibodies were visualized with avi din/biotin complex (Vectastain Elite; Vector Laboratories) using diaminobenzidine as the chromagen. For hyaluronan staining, sections were incubated with biotinylated hyaluronan binding protein (Millipore Sigma, #385911) overnight at 4 °C, followed by incubation with streptavidin HRP conjugate (Invitrogen, #434323). Staining was developed using diaminobenzidine.

[0382] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.