ATPS-59IMPROVING EFFICACY OF BEVACIZUMAB TREATMENT IN GLIOBLASTOMA BY TARGETING HIF1 ALPHA

OBJECTIVE: Glioblastomas (GBM) are highly angiogenic tumors and were initially perceived as good candidates for anti -angiogenic therapy. Bevacuzimab, a monoclonal anti-VEGF antibody, was approved by the FDA in 2009 as monotherapy for recurrent GBM, but recent phase III clinical studies revealed no overall survival benefit, yet with a small improvement on progression free survival. We have recently shown in preclinical GBM models that bevacuzimab treatment increases intratumoral hypoxia with a concomitant up-regulation of HIF 1 alpha. In the present work, we show that the non-psychoactive phytocannabinoid, cannabidiol (CBD) impairs tumor growth in several pre-clinical tumor models. Moreover, we show that CBD down regulates HIF 1 alpha under hypoxic conditions and potentiates the efficacy of anti-angiogenic therapy by inhibiting specific compensatory pathways induced by hypoxia. METHODS: Patient derived GBM spheroids were cultured under hypoxic conditions and treated with CBD. The down regulation of HIF 1 alpha and several of its downstream targets was evaluated. Furthermore GBM spheroids were implanted orthopically in nude rats. The rats were treated with either bevacuzimab, CBD or in combination. Tumor growth was assessed by MR. 18F-FMISO PET was performed to assess tumor hypoxia. RESULTS/CONCLUSIONS: Our results show that CBD treatment down-regulates HIF 1 alpha under hypoxic conditions in vitro and in vivo. Combination treatment with CBD and bevacuzimab decreases tumor growth and intratumoral hypoxia in clinically relevant human GBM xenograft models. Targeting bevacuzimab induced hypoxia by inhibiting HIF 1 alpha might be a promising combinatorial treatment strategy for the treatment of GBM.