EXTH-86. BH3 PROFILING IDENTIFIES ONC201/TIC10 AS A PROMISING PARTNER OF ABT-263 IN MEDULLOBLASTOMA IN VITRO

Abstract OBJECTIVE Medulloblastoma represents one of the most common brain tumors in children. In this study, we identified by BH3 profiling that ONC201/TIC10 sensitizes for Bcl-xL/Bcl-2 inhibition medulloblastoma and performed a preclinical testing combined treatment with inhibitor ABT-263. METHODS was to examine ONC201/TIC10-mediated dependencies on anti-apoptotic Bcl-2 family proteins. The combination ABT-263 tested different cells using MTT assays. Isobolograms were calculated characterize drug-drug interaction. Tumor spheroid chorioallantoic membrane assays used effects therapy 3D setting. Annexin V/PI staining flowcytometry detect pro-apoptotic effects. Western blot analyses knockdown experiments siRNA molecular analysis. Extracellular flux served at examining tumor cell metabolism. RESULTS showed inhibition. line finding, led predominantly synergistic inhibitory effect viability established (D425, D458, DAOY, HD-MB03), primary cultured (PC322) stem-like (SC322) 2D models. response towards independent baseline c-myc expression. On level, dose-dependent decrease Mcl-1. Moreover, caused enhanced cleavage caspases 9 3. metabolic reduction both, oxidative phosphorylation glycolytic rate reduced expression respiratory chain CONCLUSION Combined had cells. This associated downregulation resulted reprogramming which likely creates state energy deprivation.