EXTH-19. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF GLIOBLASTOMA

Abstract Over 60% of glioblastomas retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, allowing downstream pathway signaling cell fate decisions including growth inhibition death from cellular stress. We have analyzed clinical samples 10 patients newly diagnosed with glioblastoma multiforme (GBM) treated inhibitor KRT-232. detected upregulation CDKN1A transcript (a target p53) all tumors (8 10), but not p53-mutant (2 10). In patient-derived lines, treatment KRT-232 at clinically concentration was only sufficient stall tumor growth. Cell via apoptosis can be achieved when is combined chemotherapeutic agent temozolomide. As effects resistance mechanisms remain poorly understood GBM, we additionally performed genomic transcriptomic analyses lines better characterize sensitive identify putative biomarkers drug response. Dose response curves assays showed that inactivating mutations are highly resistant treatment, those exhibit various degrees sensitivity. This suggests other factors, addition mutational status, mediate gliomas. Transcriptional patient following suggest division, chromatin reorganization, differentiation state immune programs become deregulated under absence p53-inactivating mutations.