Oncology

One of the most exciting and fast emerging areas of research in the field of cannabinoid science centres on the ability of certain cannabinoids to inhibit the growth and vascular supply of cancers of various types. 

Glioma describes any tumor that arises from the glial tissue of the brain. Glioblastoma multiforme (GBM) is a particularly aggressive tumor that forms from abnormal growth of glial tissue. According to the New England Journal of Medicine, GBM accounts for approximately 50% of the 22,500 new cases of brain cancer diagnosed in the United States each year. Treatment options are limited and expected survival is a little over one year. GBM is considered a rare, or orphan, disease by the FDA and the European Medicines Agency, or EMA.

 

Clinical Research

GW commenced a Phase 1b/2a clinical trial for the treatment of Recurrent Glioblastoma Multiforme (GBM). This study follows several years of pre-clinical research conducted by GW in the field of glioma which has demonstrated that cannabinoids inhibit the viability of glioma cells both in vitro and in vivo via apoptosis or programmed cell death, may also affect angiogenesis, and have demonstrated tumor growth-inhibiting action and an improvement in the therapeutic efficacy of temozolomide, a standard treatment for glioma. In addition, GW has shown tumor response to be positively associated with tissue levels of cannabinoids. GW has identified the putative mechanism of action for our cannabinoid product candidate, where autophagy and programmed cell death are stimulated via stimulation of the TRB3 pathway.

 

This study is a 20-patient, multicentre, two part study with an open-label phase to assess safety and tolerability of GW cannabinoids in combination with temozolomide, and a double blind, randomised, placebo-controlled phase with patients randomised to active or placebo, and with a primary outcome measure of 6 month progression free survival. The study objective is to assess the tolerability, safety and pharmacodynamics of a mixture of two principal cannabinoids, THC and CBD in a 1:1 allocation ratio, in combination with temozolomide in patients with recurrent GBM. Secondary endpoints include additional pharmacokinetic and biomarker analyses and additional measurable outcomes of tumor response.

 

 

General Info: Cannabinoids in Oncology

The possibility that cannabinoids, including endocannabinoids, may treat cancer is supported by an ever increasing body of available evidence. In simple terms, cancer occurs because cells become immortalised; they fail to heed customary signals to turn off growth. A normal function of remodelling in the body requires that cells die on cue. This is called apoptosis, or programmed cell death and this process fails to proceed normally after malignant transformation. As will be discussed in greater detail below, THC, CBD, and perhaps other phytocannabinoids promote the re-emergence of apoptosis so that certain cancer cell types will in fact heed the signals, stop dividing, and die. The process of apoptosis is judged by observation of several phenomena: reduced cellular volume, condensation of nuclear chromatin, changes in distribution of phospholipids in plasma membranes, and cleavage of chromatin into DNA fragments called NDA ladders.


Another method by which tumours grow is by ensuring that they are nourished: they send out signals to promote angiogenesis, the growth of new blood vessels. Cannabinoids may turn off these signals as well. Finally, cannabinoids may display complex interactions with oncogenes. Pre-clinical studies have highlighted an anti-cancer role for phytocannabinoids via CB receptor and non-CB receptor mediated pathways in a broad spectrum of cancer types bothin vitroandin vivo. Positive data has been generated in cell lines of different cancers, although GW's main research focuses on the following:

 

glioma
prostate cancer
breast cancer

 

 

 

 

As well as treating tumour progression directly, cannabinoids have the added benefit of providing relief from secondary cancer symptoms such as (please click below to find out more):

cancer pain
anorexia and cachexia

 

Glioma

Numerous reports state that cannabinoids inhibit the viability of glioma cells both in vitro and in vivoi,ii via apoptosis or programmed cell death, and may also affect angiogenesis. One research group has established that the antiproliferative effects of CBD in multiple glioma cell lines was caused by a dramatic decrease in mitochondrial oxidative metabolism. This could be blocked by antagonism of the CB2 receptor and the effect correlated with the rate of cell death observed in the tumour linesiii. The group then went on to demonstrate that CBD also had the capability of preventing migration of tumour cells and therefore the ability for the cancer to metastasize. This effect could not be blocked by antagonists of either CB1 or CB2 receptors demonstrating that it is a non-CB receptor dependant mechanismiv.

 

References:

i. Parolaro D, Massi P, Rubino T, Monti E. Endocannabinoids in the immune system and cancer. Prostaglandins Leukot Essent Fatty Acids 2002;66(2-3):319-32.
ii. Guzman M. Cannabinoids: potential anticancer agents. Nat Rev Cancer 2003;3(10):745-55.
iii. Massi P, Valenti M, Vaccani A, Gasperi V, Perletti G, Marras E, et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. Journal of Neurochemistry February 2008;104(4):1091-11000.
iv. Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 2005;144(8):1032-6.

 

Breast Cancer

Within a mouse model of breast cancer, it has been reported that the cannabinoid Cannabidiol (CBD) is able to down regulate the presence of a protein that is elevated in tumoursiand these results have subsequently been replicated in human cancersii. The addition of the cannabinoid resulted in metastatic breast cancer cells becoming significantly less invasive and it appears that CBD is acting directly on the production of the protein. Further to these interesting findings, this group has shown that CBD is also able to inhibit proliferation of breast cancer through the modulation of a different pathway dependant upon the production of reactive oxygen species. The anti-tumour activities of a range of cannabinoids (in pure form and as extracts) have also been assessediii. In some cases, cannabinoid extracts seem to be as efficacious, if not more, than the pure cannabinoid. The study demonstrated that they exhibited this effect through a range of different mechanisms such as those that operate through the CB receptors, Transient Receptor Potential (TRP) channels and levels of intracellular calcium. This research illustrates the multi-target nature of cannabinoid compounds.

 

References:

i. Fong S, Itahana Y, Sumida T, Singh J, Coppe JP, Liu Y, et al. Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc Natl Acad Sci U S A 2003;100(23):13543-8.

ii. McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther 2007;6(11):2921-7.

iii. Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006;318(3):1375-87.

 

Prostate Cancer

Cannabinoid receptors (both CB1 and CB2) are present in significantly higher concentrations in many human prostate cancer cell linesipresenting themselves as a potential target in the treatment of this condition. In addition to this, there is published evidence pointing to a dysregulation of the endocannabinoids in prostate cancer cell lines, further supporting the potential development of cannabinoids for its treatmentii,iii. Research has shown that synthetic cannabinoids are able to inhibit the growth of cancer cells, but this effect is significantly prevented if both the CB1 and CB2 receptors are blocked by antagonistsi. Exciting new research has identified potential at TRP channels of which several phytocannabinoids have significant activity.

 

References:

i.Sarfaraz S, Afaq F, Adhami VM, Mukhtar H., Cannabinoid receptor as a novel target for the treatment of prostate cancer.  Cancer Res. 2005 Mar 1;65(5):1635-41.

ii.Bifulco M, Malfitano AM, Pisanti S, Laezza C., Endocannabinoids in endocrine and related tumours. Endocr Relat Cancer. 2008 Jun;15(2):391-408.

iii.Endsley MP, Thill R, Choudhry I, Williams CL, Kajdacsy-Balla A, Campbell WB, Nithipatikom K., Expression and function of fatty acid amide hydrolase in prostate cancer., Int J Cancer. 2008 Sep 15;123(6):1318-26

 

Cancer Pain

There is evidence that cannabinoids have promise in relieving cancer-related paini.  A Phase II/III study of Sativex demonstrated a statistically significant treatment difference from placebo for cancer-related pain in patients with end-stage cancer.  The study involved patients who were diagnosed with advanced incurable malignancy, with a mean duration of more than three years and exhibited severe levels of pain at entry to the study (greater than four on an 11-point NRS pain scale) despite ongoing treatment with currently available strong opioid analgesics, such as morphine and oxycodone up to doses as high as 1400 mgs.


Whilst opioids are the standard choice for treatment of cancer patients with moderate to severe pain, adjuvant therapy is recommended by World Health Organization (WHO) guidelines. Experiments in animal models shown that cannabinoids can interact synergistically with opioid receptor agonists in the production of antinociception.  This synergism seems to be receptor-mediated since both cannabinoid (CB) and opioid receptor antagonists can block it.  Anatomical studies have reported a similar distribution of CB1 and opioid receptors in several structures within the central nervous system (CNS), such as the brain areas implicated in nociceptive control (periaqueductal gray matter, thalamus, rostral ventromedial medulla and spinal cord).  CB1 and opioid receptors are also located on the peripheral terminals of the primary afferent neurons.  CB2 receptors are located on non-neuronal cells in inflamed tissues and inhibit the release of inflammatory mediators that excite nociceptors.  On peripheral tissues, CB1 and CB2 cannabinoid receptors have been reported to inhibit nociceptive transmission through endogenous cannabinoid tone.  Behavioral studies support an important role for peripheral CB2 receptors in animal models of persistent pain, and a synergism between these two cannabinoid receptors has been suggested in these modelsii,iii.  The presence of the three opioid receptors, mu, delta, and kappa, has been reported in peripheral tissues and endogenous opioid peptides also seem to participate in the physiological control of pain at this level.

 

References:

i. Noyes R, Brunk SF, Baram DA et al.  Analgesic effect of delta9-tetrahydrocannabinol.  J Clin Pharmacol 1975:15(2); 139-143.
ii. Cichewicz DL, Martin ZL, Smith FL, et al.  Enhancement of mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther 1998: 289; 859–867.
iii. Smith FL, Cichewicz D, Martin ZL, et al.  The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol.  Pharmacol Biochem Behav 1998: 60; 559–566.

 

Cachexia and Anorexia

Anorexia and cachexia are diagnosed in over sixty percent of advanced stage cancer patients, and are independent risk factors for morbidity and mortality. However, therapeutic regimens often prove ineffective, and the quality of life of many patients is significantly impaired by these symptomsi. In 1986, an oral THC capsule was licensed in the United States as an anti-emetic in cancer patients receiving chemotherapy. THC has also demonstrated significant stimulation of appetite and increase of body weight in HIV-positive and cancer patientsii.

 

References:

i. Tisdale MJ. Clinical anticachexia treatments. Nutr Clin Pract. 2006 Apr;21(2):168-74.
ii. Osei-Hyiaman D. Endocannabinoid system in cancer cachexia. Curr Opin Clin Nutr Metab Care. 2007 Jul;10(4):443-8.

 

Cannabinoid Publications in Oncology

 

Enhancing the activity of cannabidiol and other cannabinoids in vitro through modifications to drug combinations and treatment schedules.

Scott KA, Shah S, Dalgleish AG, Liu WM. Anticancer Res. 2013 Oct;33(10):4373-80.

 

Cannabidiol as potential anticancer drug.

Massi P, Solinas M, Cinquina V, Parolaro D. Br J Clin Pharmacol. 2013 Feb;75(2):303-12

 

Cannabidiol, a Non-Psychoactive Cannabinoid Compound, Inhibits Proliferation and Invasion in U87-MG and T98G Glioma Cells through a Multitarget Effect.

Solinas M, Massi P, Cinquina V, Valenti M, Bolognini D, Gariboldi M, Monti E, Rubino T, Parolaro D. PLoS One. 2013 Oct 21;8(10):e76918.

 

Cannabinoids: a new hope for breast cancer therapy?

Caffarel MM, Andradas C, Pérez-Gómez E, Guzmán M, Sánchez C. Cancer Treat Rev. 2012 Nov;38(7):911-8

 

Towards the use of cannabinoids as antitumour agents.

Velasco G, Sánchez C, Guzmán M. Nat Rev Cancer. 2012 May 4;12(6):436-44.

 

Cannabidiol inhibits angiogenesis by multiple mechanisms.

Solinas M, Massi P, Cantelmo AR, Cattaneo MG, Cammarota R, Bartolini D, Cinquina V, Valenti M, Vicentini LM, Noonan DM, Albini A, Parolaro D. Br J Pharmacol. 2012 Nov;167(6):1218-31.

 

Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.

Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, Di Marzo V, Izzo AA. J Mol Med (Berl). 2012 Aug;90(8):925-34.

 

A combined preclinical therapy of cannabinoids and temozolomide against glioma.

Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E, Barcia J, Guzmán M, Velasco G. Mol Cancer Ther. 2011 Jan;10(1):90-103.

 

Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action.

Lorente M, Torres S, Salazar M, Carracedo A, Hernández-Tiedra S, Rodríguez-Fornés F, García-Taboada E, Meléndez B, Mollejo M, Campos-Martín Y, Lakatosh SA, Barcia J, Guzmán M, Velasco G. Cell Death Differ. 2011 Jun;18(6):959-73.

 

Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis.

McAllister SD, Murase R, Christian RT, Lau D, Zielinski AJ, Allison J, Almanza C, Pakdel A, Lee J, Limbad C, Liu Y, Debs RJ, Moore DH, Desprez PY. Breast Cancer Res Treat. 2011 Aug;129(1):37-47.

 

The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK.

Andradas C, Caffarel MM, Pérez-Gómez E, Salazar M, Lorente M, Velasco G, Guzmán M, Sánchez C. Oncogene. 2011 Jan 13;30(2):245-52

 

Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition.

Caffarel MM, Andradas C, Mira E, Pérez-Gómez E, Cerutti C, Moreno-Bueno G, Flores JM, García-Real I, Palacios J, Mañes S, Guzmán M, Sánchez C. Mol Cancer. 2010 Jul 22;9:196

 

Molecular mechanisms involved in the antitumor activity of cannabinoids on gliomas: role for oxidative stress.

Massi P, Valenti M, Solinas M, Parolaro D. Cancers (Basel). 2010 May 26;2(2):1013-26.

 

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells.

Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, García S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, González-Feria L, Iovanna JL, Guzmán M, Boya P, Velasco G. J Clin Invest. 2009 May;119(5):1359-72.

 

Cannabinoids in intestinal inflammation and cancer.

Izzo AA, Camilleri M. Pharmacol Res. 2009 Aug;60(2):117-25.

 

Cannabinoids as potential new therapy for the treatment of gliomas.

Parolaro D, Massi P. Expert Rev Neurother. 2008 Jan;8(1):37-49.

 

Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression.

Blázquez C, Salazar M, Carracedo A, Lorente M, Egia A, González-Feria L, Haro A, Velasco G, Guzmán M. Cancer Res. 2008 Mar 15;68(6):1945-52.

 

Cannabinoids and gliomas.

Velasco G, Carracedo A, Blázquez C, Lorente M, Aguado T, Haro A, Sánchez C, Galve-Roperh I, Guzmán M. Mol Neurobiol. 2007 Aug;36(1):60-7.

 

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.

McAllister SD, Christian RT, Horowitz MP, Garcia A, Desprez PY. Mol Cancer Ther. 2007 Nov;6(11):2921-7.

 

Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis.

Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R, Alvarez L, Guzmán M, Galve-Roperh I. J Biol Chem. 2007 Mar 2;282(9):6854-62.

 

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.

Caffarel MM, Sarrió D, Palacios J, Guzmán M, Sánchez C. Cancer Res. 2006 Jul 1;66(13):6615-21.

 

A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.

Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, Sánchez C, Velasco G, González-Feria L. Br J Cancer. 2006 Jul 17;95(2):197-203.