DDDR-40. Identifying metabolic vulnerabilities of recurrent IDH1-R132H mutant glioma by high throughput screening

Abstract IDH-mutant gliomas are typically slow growing on initial presentation, however selective pressure during conventional upfront treatment with genotoxic radiation and chemotherapy can fuel the evolution of sub-populations of tumor cells. These subclones promote recurrence of IDH-mutant gliomas that are less likely to benefit from standard treatments. Therefore, novel tumor-specific therapeutic strategies with non-overlapping mechanisms are needed for durable tumor control. IDH mutant cancer cells are known to reprogram their metabolism to sustain rapid proliferation, which generate potentially targetable vulnerabilities in canonical metabolic pathways. Using the patient-derived, WHO grade 3 oligodendroglioma line TS603, we screened a small molecule library of 240 metabolism-related compounds, including both FDA-approved and non- approved drugs, over a range of 10 concentrations (1nM-20µM). Drug efficacy was assessed after 5-day incubation via cell viability assay (Cell-Titer Glo). We identified 53 compounds with IC50<2µM, including drugs that target previously reported IDH-mutant glioma targets, like NAMPT and DHODH. Notable target pathways include folate metabolism and de novo thymidylate synthesis (methotrexate, raltitrexed, 5-FU), p97 AAA ATPase/VCP chaperone (CB-5083, ML240, eeyarestatin I), mevalonate pathway (Ro 48-8071 fumarate, atorvastatin calcium), and the BCL-2 family (Navitoclax, ABT-737). We are validating these drugs across a panel of patient-derived IDH-mutant gliomasphere models, and examining the combinatorial effects of these agents with vorasidenib and CDK4/6 inhibitors. Our results provide insight into important metabolic pathway dependencies in recurrent IDH1-R132H mutant gliomas that have targeting potential.