HG-124: AUTOPHAGY MODULATION USING REPURPOSED DRUGS IN THE TREATMENT OF GLIOBLASTOMA MULTIFORME

Glioblastoma multiforme (GBM) is the most common malignant primary tumour of the central nervous system with an average patient survival mean of 15 months after treatment initiation (typically surgical excision, radiotherapy and adjuvant temozolomide). In almost 90% of all GBMs the PI3K/AKT/mTOR signalling network is activated. Consequently, the therapeutic inhibition of these pathways has been extensively investigated. Autophagy is responsible for the regulated degradation and recycling of cytoplasmic waste (such as damaged proteins or aged organelles) and is regulated by the PI3K/ATK cascade. Autophagy has been suggested to inhibit tumour progression and to potentiate the cellular response to conventional therapies. In this study, we evaluated the mechanistic effects and therapeutic potential of modulating autophagy in gliomas from ex vivo patient derived GBM cells using the re-purposed FDA approved tri-cyclic clomipramine in combination with the dual PI3K/mTOR inhibitor BEZ235. We show that ex vivo GBM cells are highly resistant to temozolomide treatment and that their dual treatment with clomipramine and BEZ235 has a synergistic anti-GBM effect in both 2D and 3D in vitro models, characterized by the induction of autophagy. This was noted at both the transcription and protein level. The results presented here offer an encouraging strategy to target apoptosis-resistant GBM by hyper-activating levels of cellular autophagy.