P10.26.B EXPLORING POTENTIAL ANTITUMOR EFFECTS OF CANNABIDIOL AND TETRAHYDROCANNABINOL IN A PATIENT-DERIVED GLIOBLASTOMA MODEL

Abstract

Abstract BACKGROUND Glioblastoma (GBM) is a CNS malignancy which is in dire need of novel treatment options. Drug repurposing has become a means to circumvent major obstacles that accompany drug development for GBM. The cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) have garnered the interest of the scientific community for the treatment of GBM as they possess pleiotropic effects in other pathologies. In the present study we are investigating potential antitumor effects of these cannabinoids by using our patient derived GBM model which recapitulates GBM in its genetic make-up and heterogeneity. MATERIAL AND METHODS To assess potential antitumor effects in vitro, we performed a screen on 20 patient derived GBM cultures to obtain a sensitivity profile for both cannabinoids. These cultures ranged in background regarding primary/recurrence and IDH mutation. To investigate effects of these cannabinoids on GBM radio-and-chemosensitivity, combination studies with either lomustine (CCNU) or irradiation (RTx) were performed on recurrent GBM cultures. The zero-interaction potential method was used to quantify synergy between the cannabinoids. The enhancement factor was used to quantify potential radiosensitization or ratio-effects between the cannabinoids. RESULTS Screening of both cannabinoids revealed CBD to possess a higher level of cytotoxicity than THC. IC50 values of CBD ranged from 2.5 - 18.5 µM and the values of THC ranged from 7.20 - 47.60 µM. In a panel of 8 cultures, combinations of CBD with THC, CBD with CCNU and THC with CCNU was tested to gain insight in combination effects. In 1/8 cultures synergy was observed between CBD and THC. In 1/8 cultures synergy between CBD and CCNU was observed and in 4/8 cultures synergy between THC and CCNU. When combined with irradiation, no enhancement was observed in any of the 4 cultures tested. No ratio-dependent enhancement between the cannabinoids was observed when combined in a 1:1, 1:4 or 4:1 ratio of CBD:THC. CONCLUSION Screening of the cannabinoids CBD and THC revealed that CBD displays a stronger cytotoxic effect than THC. Combinations of either of the two with each other or CCNU revealed moderate additive effects in the majority of cultures and synergy in a small subset. We did not observe radiosensitizing effects in our patient derived GBM model. Relating in vitro found cytotoxic concentrations to clinically achievable concentrations, we found that CBD requires approximately 3 times higher plasma concentrations and THC >40 times to achieve an antitumor effect. Currently we are investigating long term treatment effects of CBD and its mechanism of action.