Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma

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PROJECT SUMMARY/ABSTRACT – Project 2 Glioblastoma (GBM) is one of the most lethal of all cancers. This is in large part due to the inability of currently available therapies to induce significant tumor cell death. Using integrated molecular (exome and RNAseq) and functional (via BH3 Profiling) characterization of a large library of GBM patient specimens, compelling preliminary data for this project identify that all GBM tumors are comprised of two molecular intrinsic apoptotic blocks – consisting of MCL1 and BCL-xL – that drive basal GBM survival. Notably, while DNA damaging therapy (IR/TMZ) or molecularly targeted therapy (e.g., EGFR TKI) can ablate the MCL1 block in a genotype specific manner, the BCL-xL block persists ultimately driving resistance to apoptosis under these commonly used therapeutic paradigms. These exciting new results, together with complementary findings from the previous SPORE funding, has led to the hypothesis that selective targeting of BCL-xL in combination with either IR/TMZ or EGFR TKI can overcome intrinsic apoptotic resistance and induce profound GBM tumor regressions. This SPORE Project renewal will test this hypothesis through the following aims. Aim 1 will investigate whether a novel BCL-xL antagonist (in collaboration with Abbvie) with GBM specificity has anti-tumor effects when combined with TMZ/IR or a new, clinical brain penetrant EGFR TKI in preclinical GBM models. Aim 2 includes a “window of opportunity” clinical trial to explore whether these novel clinical drugs can ablate the two intrinsic apoptotic blocks in recurrent GBM patients. Finally, Aim 3 proposes to identify potential mechanisms of resistance to targeting the intrinsic apoptotic machinery in diverse preclinical GBM samples. Together, the studies proposed in this application present a new therapeutic paradigm through specific manipulation of intrinsic apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.