STEM-19. POTENTIAL THERAPEUTIC EFFECTS OF NOVEL HISTONE DEACETYLASE INHIBITORS ON HUMAN-DERIVED GLIOBLASTOMA TUMORSPHERES

Abstract

Abstract BACKGROUND Histone deacetylase (HDAC) inhibitor is a promising anticancer drug targeting epigenetic alterations on tumor cells, however, failed to prove its feasibility on glioblastoma (GBM) in several trials. We developed new HDAC inhibitors and applied them to human-derived GBM tumorsphere(TS)s to confirm its therapeutic efficacy to overcome the current limitations. Materials and METHODS The expression level of HDAC in GBM versus normal brain tissue was evaluated with RNA sequencing and its knock-down effects were evaluated through western blot, WST, and luciferase assay. The most potential drugs were selected among the candidates through dose-escalation WST assays, and their capacities on HDAC were evaluated through western blot and HDAC activity/inhibition direct assay. The results of the sphere-formation assay, 3D matrix invasion assay, and transcriptome data analysis were compared between the drugs, and bioluminescence images and Kaplain-Meier survival cure were obtained through a mouse model. RESULTS HDAC 8 is more expressed in GBM tissue and TSs than normal ones, and the knock-down of HDAC 8 shows decreases in viability, ATP levels, and related proteins. Two potential HDAC 8 inhibitors were selected and compared with suberoylanilide hydroxamic acid (SAHA) through the experiment, which discovered that they not only reduced HDAC’s expression and its activity but also stemness and invasiveness of GBM TSs to comparable levels despite the differences in transcriptional profile changes, with meaningful survival rates in a mouse model. CONCLUSION We have newly developed meaningful HDAC inhibitors in the tumorsphere stage, and believe it could be a fundamental result for improving future treatment methods.