Cross-Reference to Related Applications

[0001] The present patent application claims the benefits of priority US Provisional Patent Application No. 62/505,321, entitled "Pharmaceutical Synergistic Combinations of Cannabinoids and Terpenoids for Down Regulating Hedgehog Signaliser-Pathway, and their Use for Preventing, Inhibiting and/or Reversing Tumorigenesis, Neovascularization and/or Angiogenesis in a Mammal" and filed at the United Stated Patent and Trademark Office on May 12, 2017, the content of which is incorporated herein by reference.

Field of the Invention

[0002] The present invention generally relates to pharmaceutical compositions and their use for preventing, inhibiting and/or reversing tumorigenesis, neovascularization and/or angiogenesis in a mammal, in particular in the treatment of cancers, or ocular neovascularization and angiogenesis related ocular diseases.

Background of the Invention

Hedgehog signaling pathway and tumour cell proliferation

[0003] The Hedgehog (HH) signaling pathway is a developmental signaling pathway, highly conserved from flies to mammals, that is indispensable in the proper patterning and development of various tissues by influencing expression of target genes involved in proliferation, differentiation, self-renewal, angiogenesis, cell migration, and axon guidance. Inhibition of the HH signaling pathway in various organisms (including in humans) during early embryogenesis, both genetically and chemically, is lethal due to widespread defects in tissue patterning and organogenesis.

[0004] Conversely, over activation of the pathway is causal in the initiation, progression, and metastasis of several types of tumours in all stages of human development. HH promotes carcinogenesis by promoting tumour cell proliferation, survival, and metastasis; as well as recruitment of blood vessels by promoting angiogenesis. HH dependent tumours include medulloblastoma, basal cell carcinoma (BCC), rhabdomyosarcoma, chronic myeloid leukemia, multiple myeloma, lymphoma, breast cancer, prostate cancer, small cell lung cancer, colorectal cancer, liver cancer, or stomach cancer (reviewed by Wu, et al. 2017).

[0005] In mammals, the hedgehog signaling pathway consists of the secreted HH ligands, Sonic, Desert, and Indian HH (SHH, DHH, IHH), which interact with their receptor Patched (PTCH) to activate an intracellular signaling cascade, culminating in the translocation of the GLI transcription factors to the nucleus, where they activate target gene expression. In the absence of HH, PTCH inhibits the transmembrane protein Smoothened (SMO), resulting in an accumulation of the GLI transcription factors along with Suppressor of Fused (SUFU) at the base of the primary cilium (PC), a cytoskeletal extension of the plasma membrane that facilitates cellular response to a variety of extracellular stimuli. GLIs are phosphorylated by kinases at the base of the PC, resulting in proteolytic processing and conversion to their repressor forms (GLI ^R ), which are targeted to the nucleus to downregulate target genes. In the presence of HH, PTCH inhibition of SMO is relieved, and SMO translocates to the PC, where it promotes the PC localization of the SUFU/GLI complex. The GLI proteins are subsequently released from SUFU, and bypass proteolytic cleavage to enter the nucleus as GLI activators (GLI ^A ), where they downregulate target genes (HH signaling pathway reviewed by Briscoe and Therond 2013).

[0006] Several inhibitors of the HH pathway that target it at different points are now being investigated as therapeutic options for HH dependent cancers. Included in these inhibitors are those that target SHH protein, ciliary biogenesis, the GLI transcription factors, and SMO. SMO antagonists have been particularly successful in inhibiting tumour growth, due to the strategic location of SMO in the HH pathway. Early discoveries identified the naturally occurring cyclopamine as a potent inhibitor of SMO, and improved derivatives of cyclopamine are now undergoing clinical trials, and show promising results in downregulating tumour growth via inhibition of the HH pathway. Indeed, two small molecule SMO inhibitors, Vismodegib and Sonidegib, have been approved for use in patients with locally advanced BCC or metastatic BCC (Vismodegib only) (Wu, et al. 2017).

[0007] Despite the progress to date in identifying inhibitors of the HH pathway and utilizing them to treat HH mediated tumours, there is still a need for additional appropriate therapies in cancer growth. Therefore, identification of novel inhibitors of the HH pathway, in particular at the level of SMO, will open up possibilities for novel and improved therapies. Hedgehog signaling pathway and ocular neovascularization

[0008] Consistent with Hhs extensive role in development, there is evidence to suggest Hh regulates vertebrate vascular development and angiogenesis. Vasculogenesis refers to the formation of endothelial tubes or blood vessels de novo from newly differentiational angioblasts or endothelial precursor cells, while angiogenesis refers the formation or remodelling of new blood vessels from existing vasculature (Byrd & Grabel, 2004). In the mouse embryo, overexpression of Shh causes hypervascularization of the neuroectoderm (Ro witch, et al., 1999), while Shh-mx\\ mutants have decreased vascularization of the lung tissues (Pepicelli, et al, 1998). Vessel differentiation in the mouse visceral yolk sac is also regulated by Hh, such that Smo loss -of-function mutants display no ability to remodel vessels with dense endothelial tubules containing clusters of primitive erythrocytes attributing to early lethality (Zhang, et al, 2001; Coultas, et al, 2010). Similarly, Ihh ^' mutant yolk sacs display a less severe phenotype compared to Smo ^~ ' ^~ embryos, which is characterized by small, under developed or collapsed visceral yolk sac vessels (Byrd, et al., 2002) and a 50% survival beyond midgestational stages (St-Jacques, et al, 1999). The difference in phenotype severity between Smo ^' ' ^' and Ihh ^'A may be due partial compensation by Dhh derived from yolk sac mesoderm (Farrington, et al, 1997). Ptch-/- embryos also die embryonically due to vascular defects (Coultas, et al, 2010). In vitro embryonic stem cell models derived from Ihh ^~A or Smo ^' mutant mice or treated with pharmacological Hh inhibitors have an apparent lack of endothelial cells and primitive blood formation (Byrd, et al., 2002; Maye, et al, 2000), consistent with in vivo data. Like murine models, zebrafish embryos with mutations in Hh signaling components that disrupt Hh signaling from the midline have dysfunctional circulation and vascularization (Lawson, et al, 2002; Brown, et al., 2000), and Shh ligand from the endoderm promotes the organization of angioblasts into tube-shaped vessels (Vokes, et al, 2004).

[0009] Hh also has a described role in regulating angiogenesis in adult tissues. For example, in the adult mouse, cardiac and vascular tissues express Ptchl and respond to exogenous Hh (Pola, et al., 2001). Shh is a potent angiogenic factor in corneal and ischemic limb models, where it promotes vessel formation and improves tissue function post-injury, respectively (Pola, et al, 2001; Pola, et al, 2003). In human cancer models, where Hh pathway activation is known to promote tumorigenesis, it has been shown that Hh-responsive stromal perivascular cells drive tumor angiogenesis (Chen, et al., 2001; Pinter, et al, 2013).

[0010] The mechanism of action by which Hh regulates angiogenesis appears to be indirect through upregulation of pro-angiogenic growth factors, including vascular endothelial growth factor and angiopoietin-1 and -2, in support cells, such as adventitious fibroblasts (Chen, et al, 2001; Nagase, et al., 2006; Moran, et al, 2012; Pola, et al, 2001). The Notch (Lawson, et al, 2002; Moran, et al, 2012) and Bone morphogenic protein (BMP) (Astorga & Carlsson, 2007) pathways have also been implicated in distinct, context dependent signaling networks downstream of Hh to control angiogenesis. However; additional evidence has shown that endothelial cells can respond to Hh directly, promoting endothelial progenitor proliferation, migration, adhesion, and capillary formation (Vokes, et al., 2004; Asai, et al, 2006) through the regulation of Rho/ROCK kinase signaling and by inducing the target genes matrix metalloprotease and osteopontin (Renault, et al, 2010).

[0011] Aberrant blood vessel growth is implicated in several human diseases, particularly in the eye, such as diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, retinal vein occlusion and retinopathy of prematurity (Chirco, et al, 2017; Shin, et al, 2014; Liou, et al, 2009; Laouri, et al, 2011 ; Shazly & Latina, 2009). While disease mechanisms in each case differ, the eye is extremely vulnerable to neovascularization and inappropriate angiogenesis, which often leads to irreversible vision loss. There is limited evidence of a causative role for Hh within these ocular diseases, but it is possible that treatment methods inhibiting vessel growth by blocking this signaling pathway may have board therapeutic application in the context of ocular disease (Surace, et al, 2006; Nochioka, et al, 2016; Walshe, et al., 2011 ; Fujita, et al, 2009).

[0012] Neovascularization in the retina is causative in many retinal diseases, including diabetic retinopathy, age-related macular degeneration, neovascular glaucoma, retinal vein occlusion and retinopathy of prematurity.

[0013] Diabetic retinopathy (DR) is a common complication of diabetes mellitus, a metabolic disease distinguished by elevated blood glucose levels, that affects the microvasculature of the retina (Shin, et al., 2014). The earliest detectable type of DR, termed non-proliferative diabetic retinopathy, is characterized early by microaneurysms and retinal venous dilation, followed by intraretinal hemorrhaging and edema, which if left untreated can lead to irreversible vision loss (Liou, et al., 2009). As hyperglycemia continues, the disease progresses with widespread hemorrhages, capillary dilation, vascular permeability and intraretinal microvascular abnormalities (Liou, et al, 2009). Ischemia-induced blood vessel proliferation marks the progression of the disease to proliferative diabetic retinopathy, where new fragile and leaky vasculature is formed resulting in vitreous hemorrhaging (Liou, et al, 2009). Over time these new blood vessels tend to undergo fibrosis and contract, leading to retinal detachments, and new vessels can invade the anterior chamber causing neovascular glaucoma (Liou, et al, 2009). In addition to vascular dysfunction and edema, inflammation and oxidative stress lead to neuronal dysfunction and contribute to the disease (Shin, et al, 2014).

[0014] Neovascular Glaucoma (NVG) is a severe form of glaucoma characterized by the development of neovascularization within the iris that obstructs aqueous humor outflow and elevates intraocular pressure, leading to vision loss (Rodrigues, et al., 2016). NVG is usually secondary to posterior segment disease involving hypoxia in the retina, which promotes the growth of new blood vessels in the anterior chamber (Shazly & Latina, 2009), and thus several ocular and systemic disorders may lead to the disease.

[0015] Retinal vein occlusion (RVO) is an obstruction of the retinal venous system, classified according to where the occlusion is located, that is often caused by external compression or disease of the vein wall that can lead to visual morbidity and blindness (Laouri, et al, 2011). RVO can also be further subdivided into ischemic, where there is significant inhibition of blood flow, and non-ischemic, where there is no area of capillary non-perfusion (Laouri, et al, 2011). In ischemic RVO, ocular neovascularization is a well-established, serious complication that contributes to disease progression (Laouri, et al, 2011).

[0016] Age-related macular degeneration (AMD) is a highly prevalent and debilitating disease that affects the macula, the area responsible for high-acuity vision, in older adults (Chakravarthy, et al, 2010). AMD has two major forms: atrophic, non-exudative or dry AMD and wet, neovascular or exudative AMD. Dry AMD broadly describes all forms of AMD that are not neovascular and it is characterized by the build up of cellular debris, or drusen, between the retina and choroid layer that causes retinal pigment epithelium (RPE) geographical atrophy and retinal scarring (Chakravarthy, et al, 2010). In wet forms of AMD, the formation of aberrant subretinal or subRPE choroidal vessels, destroying the architecture of the overlying RPE and outer retina (Chirco, et al, 2017). These leaky vessels lead to intraretinal or subretinal fluid, hemorrhaging and the present of lipids that ultimately develop into a fibrotic scar and permanent central vision loss due to photoreceptor loss (Chirco, et al, 2017). Although the exact disease mechanisms remain unknown, it is postulated that wet AMD is a result of a disrupted balance between pro-angiogenic and anti-angiogenic factors (Chirco, et al, 2017). Cannabinoids are Inhibitors of the Hedgehog Pathway

[0017] Recently, it was shown that phyto-derived and endogenous cannabinoids potently inhibit the hedgehog pathway by directly antagonizing SMO activity (Khaliullina, et al., 2015). In this study, addition of either endocannabinoids, including 2-acylglycerol an anandamide, or the phytocananbinoids THC or CBD inhibited Gli-dependent Hh signaling in both an invertebrate fly and mammalian cell model (Khaliullina, et al., 2015), which points to an evolutionarily conserved role of cannabinoids in the regulation of Hh signaling.

[0018] The endocannabinoid system (ECS) is an endogenous signaling system consisting of secreted neuromodulatory lipids (termed "endocannabinoids") anandamide and 2- Arachidonoylglycerol (2 -AG) and their receptors, cannabinoid receptor 1 and cannabinoid receptor 2 (CB1 and CB2), plus a number of alternative receptors. The ECS is active in many tissues with CB1 receptors found predominantly found in neurons in the CNS, while CB2 receptors are found in numerous peripheral tissues, including the peripheral nervous system and the immune system (Turcotte, et al. 2016; Kendall and Yudowski, 2017).

[0019] The CB receptors (CBRs) are additionally potently targeted by synthetic cannabinoids and phytocannabinoids, the latter of which are found predominantly in various species of the Cannabis genus. Cannabis also contains numerous flavonoids, terpenoids, and phenolic compounds. Terpenoids are unique essential oil components found within plants with diverse pharmacology (Russo, 2001). Terpenoids represent thelargest group of plant chemicals, with approximately 20 000 fully characterized (Langenheim, 1994). They are subcategorized into mono-, di- and sesquiterpenoids based on their chemical structure (Russo, 2001), and it has been proposed terpenoids synergize with phytocannabinoids to influence ECS pathway activation in an effect termed "the entourage effect" - first described by Mechoulam and Ben- Shabat (1999). Although this effect has been difficult to quantify, it is derived from the fact that botanical extracts are more efficacious than the natural products in isolation (Carlini, et al, 1974; Russo, 2001).

[0020] Reflective of the ubiquitous expression the ECS, the art contains various clinical and preclinical studies the therapeutic potential of the ECS in a variety of contexts, including in nociception (Kim and Fishman 2017), nausea (Rock and Parker 2016), epilepsy (Rosenberg, Patra and Whalley 2017), inflammation (Turcotte, et al. 2016), and importantly, cancer (Ladin, et al. 2016).

[0021] Exogenous cannabanoids and terpenoids have been identified as potent anti -tumour agents in many preclinical studies, acting via four common mechanisms: promoting apoptosis, inhibiting proliferation, inhibiting metastasis, and inhibiting angiogenesis (Ladin, et al. 2016). Interestingly, several studies have reported that extracts containing a mixture of cannabinoids and terpenoids exert more potent anti-carcinogenic effects than do single purified cannabinoids (Ladin, et al. 2016).

[0022] There are many types of cancer that have been shown in the art to be sensitive to cannabinoids and terpenoids, including prostate cancer, cervical cancer, glioblastoma multiforme, neuroblastoma, astrocytoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, lymphoma, and bladder cancer (Ladin, et al. 2016).

[0023] Given the known anti-carcinogenic properties of various cannabinoids and their potentiation by terpenoids, the observation that cannabinoids can modulate the HH signaling pathway, a known oncogenic pathway when aberrantly upregulated, provides an intriguing novel class of therapeutic molecules that to date have not been investigated in terms of their effectiveness in treating HH mediated diseases. Furthermore, small molecule inhibition of the HH pathway and its effectiveness in treating human disease is well known in the art, however additional molecules need to be identified and developed to provide more appropriate therapies.

Objects of the Invention

[0024] Therefore, the objective of the present invention was to identify a novel combination of molecules, in particular a synergistic combination of cannabinoids and terpenoids, that can down regulate hedgehog (HH) pathway, in particular HH-pathway mediated cellular proliferation leading to tumour growth and cancer, and Hh pathway mediated cellular proliferation, differentiation, adhesion, and/or migration leading to ocular neovascularization and angiogenesis.

[0025] Other and further objects and advantages of the present invention will be obvious upon an understanding of the illustrative embodiments about to be described or will be indicated in the appended claims, and various advantages not referred to herein will occur to one skilled in the art upon employment of the invention in practice.

Summary of the Invention

[0026] The shortcomings of the prior art are generally mitigated by novel pharmaceutical compositions comprising a synergistic combination of one or more cannabinoids and one or more terpenoids, and their use for down regulating hedgehog (HH) pathway in a mammal, in particular in a human being, in order to prevent, inhibit and/or reverse cell proliferation, adhesion, differentiation and/or migration in a mammal.

[0027] According to a preferred embodiment, it is disclosed pharmaceutical compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid, and their use for down regulating hedgehog (HH) pathway in a mammal, in particular in a human being. Understandably, the present invention is not limited to pharmaceutical compositions of plant extracts as pharmaceutical compositions using synthetic plant extract such as synthetic cannabinoids may be used.

[0028] According to a preferred embodiment, it is disclosed pharmaceutical compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid, and their use as anti-carcinogenic agents.

[0029] According to a preferred embodiment, it is disclosed pharmaceutical compositions of plant extracts comprising a synergistic combination of at least one cannabinoid and at least one terpenoid, for treating tumours dependent on deregulated Hedgehog signaling pathway.

[0030] According to a preferred embodiment, it is disclosed pharmaceutical compositions of plant extracts comprising a synergistic combination of at least one cannabinoid and at least one terpenoid, for inhibiting and/or reversing ocular disease related with ocular neovascularization and/or angiogenesis in a mammal.

[0031] According to a preferred embodiment, it is disclosed a method of preventing, inhibiting and/or reversing tumour proliferation in a mammalian subject by administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse cancer.

[0032] Preferably, the pharmaceutical compositions described herein are used in the treatment of HH-dependent medulloblastoma, basal cell carcinoma, rhabdomyosarcoma, chronic myeloid leukemia, multiple myeloma, lymphoma, breast cancer, prostate cancer, small cell lung cancer, colorectal cancer, liver cancer, or stomach cancer.

[0033] Preferably, the treatment of said tumours with the medicaments results in a reduction, amelioration, and or reversal in tumour cell proliferation, survival, or metastasis, or a reduction, amelioration, and or reversal in blood vessel invasion to the tumour.

[0034] According to a preferred embodiment, it is disclosed a method of preventing, inhibiting and/or reversing ocular disease related with ocular neovascularization and angiogenesis in a mammalian subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular disease.

[0035] According to a preferred embodiment, it is disclosed the use of a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse tumour proliferation in a mammal.

[0036] According to a preferred embodiment, it is disclosed the use of a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to make a medicament to prevent, inhibit and/or reverse tumour proliferation in a mammal.

[0037] According to a preferred embodiment, it is disclosed a method of preventing, inhibiting and/or reversing ocular disease related with ocular neovascularization and angiogenesis in a mammalian subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular disease.

[0038] According to a preferred embodiment, it is disclosed the use of a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to prevent, inhibit and/or reverse ocular neovascularization and angiogenesis related ocular diseases in a mammal.

[0039] According to a preferred embodiment, it is disclosed the use of a therapeutically effective amount of a pharmaceutical composition comprising a synergistic combination of one or more cannabinoids and one or more terpenoids that interfere with the hedgehog signaling pathway, to make a medicament to prevent, inhibit and/or reverse ocular neovascularization and angiogenesis related ocular diseases in a mammal.

[0040] According to a preferred embodiment, said ocular neovascularization and angiogenesis related ocular diseases may be selected from the group consisting of age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma and retinal vein occlusion. [0041] According to a preferred embodiment, said pharmaceutical compositions comprise a synergistic combination of one or more endogenous, synthetic, or phyto-derived cannabinoids and one or more terpenoids.

[0042] According to a preferred embodiment, said one or more phytocannabinoids are selected from the group consisting of Cannabichromene (CBC), Cannabichromenic acid (CBCV), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerol propyl variant (CBGV), Cannabicyclol (CBL), Cannabinol (CBN), Cannabinol propyl variant (CBNV), Cannabitriol (CBO), Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), Tetrahydrocannabivarinic acid (THCVA), and a mixture thereof.

[0043] According to a preferred embodiment, said one or more terpenoids is a mono-, di-, or sesquiterpene.

[0044] According to a preferred embodiment, the pharmaceutical composition may be derived from combinations of isolated cannabinoids or terpenoids derived from the flowers, roots, seeds, or leaves of species of the Cannabis genus. Understandably, the cannabinoids may be from various origins, such as but not limited to plant extract or synthetically derived.

[0045] According to a preferred embodiment, the medicament is derived from inhaling smoke from combusting dried flowers from the Cannabis plant.

[0046] In another non-limiting embodiment of the invention, the medicament is derived from inhaling vapour from heating an extract from the Cannabis plant.

[0047] In another non-limiting embodiment of the invention, the medicament is in a form of a cream, ointment, solution or foam applied topically and is comprised of combinations of cannabinoids and terpenoids; and optionally at least one pharmaceutical acceptable carrier or excipient.

[0048] In another non-limiting embodiment of the invention, the medicament is in a form of a pill comprising a combination of cannabinoids and terpenoids and at least one pharmaceutical acceptable carrier or excipient.

[0049] In another non-limiting embodiment of the invention, the medicament is in a form of a suppository comprising a combination of cannabinoids and terpenoids and at least one pharmaceutical acceptable carrier or excipient.

[0050] In another non-limiting embodiment of the invention, the medicament is in a form of a strip or tablet, such as a mucoadhesive strip or tablet comprising a combination of cannabinoids and terpenoids and at least pharmaceutical acceptable carrier or excipient.

[0051] In another non-limiting embodiment, the medicament further comprises one or more Fatty Acid Amide Hydrolase inhibitor (FAAH), a monoacylglycerol lipase (MAGL) inhibitor and/or one or more HH pathway inhibitor.

[0052] In another non-limiting embodiment, the medicament is used in combination or as an adjunct therapy to a chemotherapeutic agent.

[0053] According to a preferred embodiment, said pharmaceutical composition is delivered by intraocular injection.

[0054] According to a preferred embodiment, said pharmaceutical composition is delivered by intraocular implant.

[0055] According to a preferred embodiment, said pharmaceutical composition is delivered by direct contact with the cornea via eye drops or gels.

[0056] According to a preferred embodiment, said pharmaceutical composition contains one or more terpenoids and cannabinoids encapsulated in a liposome.

[0057] According to a preferred embodiment, said pharmaceutical composition downregulates or inhibits one or more components of the hedgehog signaling pathway within retinal vasculature and surrounding support cells of the ocular tissue.

[0058] Other and further aspects and advantages of the present invention will be obvious upon an understanding of the illustrative embodiments about to be described or will be indicated in the appended claims, and various advantages not referred to herein will occur to one skilled in the art upon employment of the invention in practice.

[0059] The features of the present invention which are believed to be novel are set forth with particularity in the appended claims.

Detailed Description of the Preferred Embodiment

[0060] A novel pharmaceutical compositions and method of using the same for the treatment of cancers will be described hereinafter. Although the invention is described in terms of specific illustrative embodiments, it is to be understood that the embodiments described herein are by way of example only and that the scope of the invention is not intended to be limited thereby.

Terminology

[0061] The terminology used herein is in accordance with definitions set out below. [0062] As used herein % or wt.% means weight % unless otherwise indicated. When used herein % refers to weight % as compared to the total weight percent of the phase or composition that is being discussed.

[0063] By "about", it is meant that the value of weight %, time, or temperature can vary within a certain range depending on the margin of error of the method or device used to evaluate such weight %, time, concentration or temperature. A margin of error of 10% is generally accepted.

[0064] By "room temperature", it is meant the temperature where the compositions are made and stored. A room temperature of between about 15 and 25 °C is generally accepted.

[0065] It is fist disclosed pharmaceutical compositions of plant extracts comprising a combination of at least one cannabinoid and at least one terpenoid.

[0066] The one or more phytocannabinoids are selected from the group consisting Cannabichromene (CBC), Cannabichromenic acid (CBCV), Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabidivarin (CBDV), Cannabigerol (CBG), Cannabigerol propyl variant (CBGV), Cannabicyclol (CBL), Cannabinol (CBN), Cannabinol propyl variant (CBNV), Cannabitriol (CBO), Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid (THCA), Tetrahydrocannabivarin (THCV), Tetrahydrocannabivarinic acid (THCVA), and a mixture thereof.

[0067] The above cannabinoids are illustrated herein after:

CBC Cannabichromene

CBCV Cannabichromenic acid

CBD Cannabidiol CBDA Cannabidiolic acid

CBDV Cannabidivarin

CBG Cannabigerol

CBGV Cannabigerol propyl variant

CBL Cannabicyclol

CBN Cannabinol

CBNV Cannabinol propyl variant CBO Cannabitriol

THC Tetrahydrocannabinol

THCA Tetrahydrocannabinolic acid

THCV Tetrahydrocannabivarin

THCVA Tetrahydrocannabivarinic acid

[0068] In accordance with a preferred embodiment the one or more cannabinoids are selected from those that bind and activate the endocannabinoid receptors to influence the Hh receptor SMO, or those have an inhibitory effect on Hh signaling pathway, such as:

· phytocannabinoids, preferably showing an inhibitory effect on Hh signaling in Light II cells and drosophila wing discs, such as, but not limited to:

^■ THC,

^■ CBD,

^■ CBN, or ^■ a mixture thereof; and/or

• Phytocannabinoid, preferably influencing endocannabinoid metabolism; therefore, indirectly modulating Hh signaling through this mechanism or by directly modulating Hh signaling through an alternative mechanism, such as, but not limited to:

^■ CBC,

^■ CBDV,

^■ THCV,

^■ CBG, or

^■ a mixture thereof; and/or,

• synthetic cannabinoids, preferably acting as potent cannabinoid receptor agonists and preferably retaining the ability to inhibit Hh activity at the cellular level, such as, but not limited to:

^■ CBD-DMH

^■ JW015,

^■ Win55,212-2,

^■ N-palmitoylethanolamine,

^■ JWH133,

^■ HU-210,

^■ HU-308,

^■ HU-433,

^■ CP55940, or,

^■ A mixture thereof; and/or

• endocannabinoids, preferably showing an inhibitory effect on Hh signaling in Light II cells and drosophila wing discs such as, but not limited to:

^■ 2-acylglycerol 20:4,

^■ N-acylserine 20:4,

^■ N-acylethanolamide 16:0,

^■ N-acylethanolamide 16: 1,

^■ N-acylethanolamide 18:0,

^■ N-acylethanolamide 18: 1,

^■ N-acylethanolamide 18:2, N-acylethanolamide 20:4,

N-acyldopamine 16:0,

N-acyldopamine 18:0,

N-acyldopamine 20:4,

2-alkylglycerol 20:4, or

a mixture thereof.

[0069] In another embodiment, the inhibition of Hh signaling may indirectly occur through the modulation of endocannabinoid metabolism or through modulation of any other pathways/molecular targets. In yet other embodiments, the inhibition of Hh signaling may further directly occur a through Hh pathway modulation via the Hh receptor SMO.

[0070] In accordance with a preferred embodiment, it is disclosed an effective amount of said one or more cannabinoids ranging from, but not limited to, about ΙΟηΜ to about lOOmM.

[0071] In accordance with a preferred embodiment, the one or more terpenoids are, but not limited to:

a. Pinene; (l S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene-(lS,5S)-6,6-di methyl- 2-methylenebicyclo[3.1. l]heptane;

b. Humulene: 2,6,6,9-Tetramethyl-l,4-8-cycloundecatriene

c. Limonene: l-Methyl-4-(l-methylethenyl)-cyclohexene

d. Myrcene: 7-Methyl-3-methylene-l,6-octadiene

e. Linalool : (3,7-dimethylocta-l,6-dien-3-ol); f. β-caryophyllene: (lR,4E,9S)-4,l l,l l-Trimethyl-8-methylidene- bicyclo[7.2.0]undec-4-ene

g. Phytol: (2E,7R,l lR)-3,7,l l,15-tetramethyl-2-hexadecen-l-ol;

h. Betulinic acid: (3P)-3-Hydroxy-lup-20(29)-en-28-oic acid

i. Geraniol: (Z)-3,7-Dimethyl-2,6-octadien-l-ol, or

j . a mixture thereof.

[0072] Advantageously, the above-listed terpenoids are abundant in cannabis or other plant sources, and have previously described anti-cancer or angiogenic properties.

[0073] In accordance with a preferred embodiment, it is disclosed an effective amount of said one or more terpenoids ranging from, but not limited to, about ΙΟηΜ to about 5μΜ. [0074] The pharmaceutical composition may further comprise one or more pharmaceutical acceptable carrier or excipient comprising: antiadherents, binders, coatings, colours, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, vehicles.

[0075] While illustrative and presently preferred embodiments of the invention have been described in detail hereinabove, it is to be understood that the inventive concepts may be otherwise variously embodied and employed and that the appended claims are intended to be construed to include such variations except insofar as limited by the prior art.

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