Project 2: Overcoming GBM RT-resistance

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PROJECT SUMMARY/ABSTRACT (Project 2) Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy, radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT-resistance to further improve patient outcomes. GBM cells exhibit profound cancer-specific metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion and survival. We have found that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. Recently, we have discovered that non-malignant cells in the GBM microenvironment promote purine metabolism and RT resistance in glioma cells. In this research proposal, we will (1) determine the metabolic mechanisms by which non-malignant cells regulate GBM metabolism and RT resistance, (2) measure the activity of these metabolic pathways in GBM tumors in patients and (3) interrupt this regulation in patients with GBM by combining an FDA-approved and CNS-penetrant inhibitor of purine metabolism with standard of care RT and temozolomide in a phase 1B clinical trial.