Glioblastoma multiforme (GBM) is an incredibly aggressive and almost universally fatal disease. 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 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.
CBD as an Adjunct to Standard of Care Treatment
Some early evidence suggests that CBD may be effective in treating certain cancers, including GBM. It was previously shown that GBM 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).
Additional research is needed to evaluate the potential efficacy of CBD in patients with glioblastoma mutilforme.