Glioblastoma multiforme (GBM) is an incredibly aggressive and almost universally fatal disease. Even with the most extensive surgical resections and the most aggressive radiation and chemotherapy regimens, median overall survival is as low as 15- to 19- months (Stupp, NEJM, 2005). This is likely due, in part, to the intrinsic propensity for treatment resistance and, as a result, the essentially unavoidable event of tumor recurrence. The current prognosis for most patients necessitates significant advances in the standard of care to improve both overall survival and patient quality of life.
Cannabidiol (CBD) has been shown to influence many of the key pathways involved in GBM pathogenesis – from tumor stemness and proliferation to angiogenesis and local invasion. The prospect of CBD used in combination with other pharmacologic interventions holds great promise for the treatment of GBM. The development of clinical trials to evaluate the efficacy of CBD combination therapies may represent an important step towards improving the clinical outcomes in a population of patients with few other effective therapeutic options.
About Glioblastoma Multiforme
Glioblastoma, alternatively called glioblastoma multiforme, is the most aggressive malignant tumor of the central nervous system. GBM arises from a specific type of glial cell called astrocytes, which support the survival and function of the surrounding neurons. The World Health Organization (WHO) grades gliomas on a scale of I-IV based on the degree of histopathologic atypia observed. GBM receives the most malignant designation, WHO Grade IV, for the presence of many abnormal, actively dividing cells, new vessel growth, and necrosis (Louis, Acta Neuropathol, 2016).
GBM is relatively rare, with a worldwide incidence of less than 10 cases per 100,000 people (Hanif, Asian Pac J Cancer Prev, 2017). Nonetheless, the impact of GBM is profound – they are largely incurable with only 5-10% of patients surviving five years after diagnosis (Chien, Front Public Health, 2016). With such a poor prognosis and relatively few effective interventions, new therapies are desperately needed to improve outcomes and survival.
The symptoms of GBM are relatively non-specific and often depend on the size and location of the tumor. In general, symptoms can include headache, seizure, and focal neurologic deficits that correlate with tumor location, such as weakness, language deficits, and cognitive impairment (Chang, JAMA, 2005). Ultimately, GBM is usually detected by MRI and officially diagnosed by tissue biopsy, which can occur during surgical removal of the tumor or during a separate procedure (Glioma, Mayo Clinic).
The clinical course of GBM patients depends on several factors intrinsic to the tumor itself. GBM can develop from a pre-existing, lower grade brain tumor called an astrocytoma or can arise de novo. These GBM subsets differ in their underlying pathogenesis and in disease phenotype. Sporadic GBM are the most common subtype, comprising 90% of all GBM. They typically present later in life, develop much more rapidly, and have an overall worse prognosis (Ohgaki & Kleihues, Am J Pathol, 2007; Ohgaki & Kleihues, Clin Cancer Res, 2013).
Several common genetic mutations underlie both primary and secondary GBM, including loss of tumor suppressor function on chromosome 10q and of the TP53 gene, both of which permit dysregulated cell growth and division (Ohgaki & Kleihues, Am J Pathol, 2007; Ohgaki & Kleihues, Clin Cancer Res, 2013; Rasheed, Oncogene, 1995). Additional mutations are involved in the progression from low grade astrocytomas to malignant GBM. Perhaps two of the most well-researched mutations are those occurring in IDH1 and IDH2, which segregate almost exclusively in secondary GBM (Ohgaki & Kleihues, Clin Cancer Res, 2013). IDH1/2 encodes the isocitrate dehydrogenase, which is critical for energy metabolism in the cell. Although the mechanism is not fully understood, it is thought the IDH1/2 mutations result in malignant transformation either through the production of an oncogenic metabolite or through inhibition of wild-type protein function (Bunse, Nat Med, 2018; Zhao, Science, 2009). Interestingly, possession of mutated IDH1/2 is an independent, beneficial prognostic marker, which may account, at least in part, for the differences in outcomes between primary and secondary GBM (Sanson, J Clin oncol, 2009; Weller, J Clin Oncol, 2009).
Another major contributor to the poor prognosis in these patients is the presence of a subpopulation of glioma stem cells (GSCs) within the tumor. GSCs are able to self-renew and produce a host of proteins and growth-factors that support proliferation, angiogenesis, and local tumor invasion (Liebelt, Stem Cells Int, 2016). GSCs are notoriously difficult to eradicate with the traditional therapeutic regimen, and as such, they are thought to account for treatment resistance and the nearly inevitable recurrence of disease (Bao, Nature, 2006).
GBM is typically managed by a combination of surgical resection, radiation, and chemotherapy. When possible, gross total resection with preservation of neurologic function is the preferred intervention, as it confers a more favorable outcome than subtotal resection (Noorbakhsh, J Neurosurg, 2014). After surgical intervention, most patients are treated with adjuvant radiation and chemotherapy, specifically with the alkylating agent temozolomide. Response to temozolomide largely depends on the methylation status of the MGMT gene (Zhao, World J Surg Oncol, 2016). Methylated MGMT prevents DNA repair in response to alkylating agents, allowing the tumor cell to accumulate more damage and be sensitized to chemotherapy. Presence of MGMT methylation improves overall survival by about 50% (Zhao, World J Surg Oncol, 2016).
It is important to keep in mind that GBM has a poor prognosis regardless of tumor subtype and genetic makeup. The survival benefit conferred by any one beneficial prognostic factor is a matter of months. While this can, of course, be meaningful to patients, there is a clear opportunity for improvement upon the current standard of care in order to prolong survival and improve quality of life.
Cannabidiol (CBD) as an Adjunct to Standard of Care Treatment
CBD may be effective in treating many cancers, including GBM. It was previously shown that GBM highly expresses one of the cannabinoid receptors, CB2, through which CBD and other cannabinoids are thought to exert their anti-tumor effects (Ellert-Miklaszewska, Adv Exp Med Biol, 2013). Subsequent in vitro and in vivo studies have further supported the use of cannabinoids in the treatment of GBM. Specifically, CBD was able to reduce proliferation and survival of GBM cell lines through both cell cycle arrest and the induction of programmed cell death, or apoptosis (Marcu, Mol Cancer Ther, 2010). Cannabinoids have been shown to promote apoptosis through the overproduction of a lipid subset, called ceramides, as well as through the generation unstable oxygen molecules termed reactive oxygen species (ROS) (Dumitru, Front MOl Neurosci, 2018). Accumulation of intracellular ceramides inhibits anti-apoptotic signaling molecules, while the presence of reactive oxygen species can damage nearby molecules to trigger cell death. These findings were recapitulated in a murine model of GBM, in which mice underwent intracranial injection of a GBM cell line followed by treatment with CBD or a vehicle control. Mice that were treated with CBD demonstrated a 95% reduction in tumor area (Soroceanu, Cancer Res, 2013).
CBD was also shown to modulate other key aspects of cancer. For instance, characteristic features of GBM include its propensity for local tissue invasion and profound neovascularization, which is likely secondary to overexpression of certain growth factors, such as vascular-endothelial growth factor (VEGF) (Dumitru, Front MOl Neurosci, 2018). Glioma cell lines treated with CBD downregulated expression of VEGF and other key enzymes (MMP-9 and TIMP-4) involved in digesting the extracellular matrix to allow for tumor invasion (Solinas, PLoS One, 2013). CBD also reduced the ability of glioma cells to invade through brain slices ex vivo (Soroceanu, Cancer Res, 2013).
Lastly, several studies have demonstrated that CBD can impact the stemness of glial stem cells, which are thought to be responsible for resistance and tumor recurrence, as described above. Specifically, CBD was shown to downregulate certain stem cell markers and promote differentiation of glial stem cells, which effectively shifts these cells away from their self-renewing, pro-tumorigenic phenotype (Soroceanu, Cancer Res, 2013; Nabissi, Int J Cancer, 2015).
Merits of a Cannabinoid Combination Therapy
While CBD may impact the malignant behavior of GBM cells, there is also evidence to suggest that CBD in combination with other drugs and interventions may have a more pronounced anti-tumor effect than CBD alone.
For instance, although radiotherapy is one of the mainstays of treatment for GBM, not all cancer cells respond equally to irradiation. It was recently shown that pre-treatment of multiple glioma cell lines with a combination of CBD and THC prior to irradiation substantially increased their responsiveness to this intervention (Scott, Mol Cancer Ther, 2014). Similarly, in mice with glioma xenografts, which comprise subcutaneously injected glioma cells, co-administration of THC, CBD, and temozolomide substantially reduced tumor size, even in those tumors resistant to temozolomide alone (Torres, Mol Cancer Ther, 2011). Given that treatment resistance is a common occurrence in GBM, these findings may have significant implications for the future management of GBM.
Additional evidence also suggests a beneficial, anti-tumor effect of the combination of CBD with the cholesterol epoxide hydrolase (ChEH)/antiestrogen-binding site (AEBS) inhibitors, clomiphene citrate and DPPE. These drugs are thought to exert their anti-tumor effects through the promotion of apoptosis and the sensitization to chemotherapeutic drugs, respectively. Clomiphene citrate in isolation was previously shown to induce apoptosis in GBM cell lines, particularly in those expressing IDH1 mutations (Tan, Front Pharmacol, 2018). Recently, both DPPE and clomiphene citrate were shown to synergistically reduce cell viability in multiple cancer cell lines, including gliomas (WO2017072773A1). One of the advantages of this synergistic behavior between CBD, standard of care therapies, and the ChEH/AEBS inhibitors is that it may allow for sub-maximal dosing of each of these agents. As a result, this could potentially reduce the side effects associated with both radiation therapy and temozolomide.
Taken together, preclinical data supports the continued investigation of CBD alone and in combination for the treatment of GBM.
Jay Pharma researchers have designed a clinical trial to assess the efficacy of CBD in combination with DPPE/Clomiphene Citrate in patients with GBM. The impact of combination therapies seeks to improve outcomes in patients with this devastating disease.