DDIS-22. DRUG SCREEN IN PATIENT-DERIVED IDHMUT GLIOMA STEM CELLS IDENTIFIES SEVERAL FDA-APPROVED ANTINEOPLASTIC AGENTS

Abstract

Abstract OBJECTIVE The discovery of the Isocitrate Dehydrogenase (IDH) mutation in glioma has led to a paradigm shift on how we see glioma biology. While it is clear, that IDH mutated (IDHmut) and wildtype (IDHwt) tumors have to be viewed as separate entities, the underlying biological differences are still matter of extensive research. Difficulties in cultivating IDHmut glioma stem cells (GSC) have led to a paucity of preclinical models in IDHmut glioma making the discovery of new effective chemotherapeutic agents problematic. We therefore sought to perform a repurposing drug screen in five patient-derived IDHmut GSC lines to discover potential effective antineoplastic agents, already approved by the FDA. METHODS Patient tumor tissue was obtained in our neurosurgical department to isolate and establish IDHmut GSC lines. (D)-2-hydroxyglutarate (2HG) levels were measured in the cell culture supernatant of IDHmut GSCs using an enzymatic diaphorase/resazurin system. The drug library provided by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) consisting of 146 FDA-approved drugs was used for the screen. Cell viability was assessed with the CellTiterGlo assay (Promega). RESULTS Despite several passages, the IDHmut GSCs showed stable production of 2HG and were therefore suitable for the drug screen. Cells were cultured as neurospheres and subjected to the test compounds for 72h in concentrations ranging from 0.1nM – 1µM. We identified several compounds in two IDHmut GSC lines (NCH551b, NCH1681) that had a half maximal inhibitory concentration (IC50) below 1µM and could confirm its cytotoxic potential in additional three IDHmut GSC lines (NCH612, NCH620, NCH3763). CONCLUSION In this study, we present a feasible preclinical model for a high-throughput drug screen in patient-derived IDHmut GSCs and identified several FDA-approved antineoplastic agents which warrant further investigations.