ARTICLE A novel cannabinoid formulation for glioblastoma treatment

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The goal of finding a “cure” for cancer has recently been replaced with the aim of taming tumour malignancy, turning cancer into a chronic disease with prolonged life expectancy and an improved quality of life. This strategy has been successful in some cancers; however, for glioblastoma, one of the most aggressive cancers, average survival has only increased by around 15 percent over the last 20 years.

Glioblastoma remains one of the most malignant cancer types despite the modern modalities of chemotherapy and irradiation treatment. Several phytochemicals exhibit important properties against this form of cancer, including the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from Cannabis sativa. These bind to specific transmembrane proteins which are highly expressed on the tumour cell surface and facilitate entrance into the glioblastoma cells. Once inside, the cannabinoids interfere with specific biochemical pathways, promote tumour cells’ growth arrest, inhibit their invasion and cause cell death. In over 20 animal studies, CBD/THC was found to drastically decrease the size of and even eliminate glioblastoma. Furthermore, in a few clinical trials and published reports, the variable anti-glioblastoma effects of these two cannabinoids, in combination with other therapeutic modalities, have been demonstrated. However, wider clinical application of these preparations is hindered due to the psychotropic effects of THC. This often limits the clinical usage of THC and CBD mixtures in glioblastoma patients as many will already present with adverse neuropsychiatric symptoms, including impaired cognition.

The aim of the MGC research teams from the NIB, in collaboration with the Neurosurgery Department at the University Medical Centre in Ljubljana, Slovenia, was to develop cannabinoid formulations and define protocols for the treatment of glioblastoma patients, focusing on glioblastoma stem cell (GSC) antagonists. These include the most effective cannabinoid combinations alone and with the standard therapeutic, temozolomide (TMZ). Specifically, their aim was to assess the influence of three natural cannabinoids – THC, CBD and cannabigerol (CBG) – on cell viability and apoptosis in vitro in three-dimensional (3D) spheroids and in vivo in experimental animals.

Addressing current challenges in glioblastoma therapy

The MGC research team established a postoperative, pre-treatment diagnostic platform, where the response of patients’ primary tumour cells to the most effective cannabinoid preparation was determined and correlated with the individual tumour cells’ genetics. This diagnostic platform is highly innovative as it addresses the three major reasons for inefficacy in current glioblastoma therapy.

The first obstacle is glioblastoma heterogeneity. The MGC scientists assumed that in vitro tumour cell responses may be different in each patient: 1) they would have one of four specific glioblastoma subtype tumours or 2) a unique pattern of at least five major cannabinoid cell surface receptors. If, and when, a correlation is observed using bioinformatic tools, such information would enable a patient-tailored cannabinoid formulation to be applied in his/her treatment, administered at an early stage. This may be relevant when translated to Phase I clinical trials.

This diagnostic platform is highly innovative as it addresses the three major reasons for inefficacy in current glioblastoma therapy”

Secondly, it is generally not known if and how patients’ GSCs are affected by various cannabinoids. This sub-population of cancer cells, which evolve during cancer progression by acquiring intrinsic resistance to irradiation, is at present considered the key therapeutic target. We, and others, have demonstrated CBD cytotoxic killing of GSCs whereby CBD induces an increase in damaging free radicals and others that led to the inhibition of GSCs dedifferentiation, death in vivo and even prolonged the survival of tumour-bearing mice by CBD.

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The aim of the present research was to use specific cannabinoids to develop in vitro formulations and define the protocols for the treatment of glioblastoma alone in the first phase of treatment, rather than as a “second or last choice”. We believe, based on current knowledge, that combinatorial therapy is needed in all cancers and that cannabinoids will serve to be an add-on therapeutic, with the main advantage to lower doses of harmful chemotherapy and irradiation.

No significant side effects of CBD have been observed in glioblastoma patients, however unpredictable THC effects should be avoided. Our study is the first to open the possibility of replacing THC with CBG, which is highly effective in killing GSCs – the “root” of the tumour growth. The question of specific ratios, customised to patient tumour genetics, will be addressed after a statistically relevant number of glioblastoma patients have been included in this study. To conclude, targeting GSCs with these cannabinoids may significantly improve standard disease treatment for glioblastoma.


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