EXTH-82. THERAPEUTIC TARGETING OF EZH2 AND BET BRD4 IN PEDIATRIC RHABDOID TUMORS

Abstract BACKGROUND Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), each potentially a possible therapeutic target treating AT/RT. Thus, targeting distinct histone modifier activities would be effective approach METHODS The effects inhibition on modification, cell proliferation, invasion were analyzed by immunoblotting, MTS assay, colony formation assay. RNA- chromatin immunoprecipitation-sequencing used to determine transcriptional epigenetic changes in AT/RT cells treated with inhibitors. We mice bearing human xenografts Intracranial growth was monitored bioluminescence imaging, response evaluated animal survival. RESULTS showed elevated levels trimethylation (H3K27me3) acetylation (H3K27ac), expression BRD4, lack SMARCB1 proteins. Targeted reduced proliferation invasiveness association decreasing H3K27me3 H3K27ac. Differential genomic occupancy H3K27ac regulated specific gene inhibitions. Genes associated DNA-repair pathway downregulated upon inhibition, sensitivity cisplatin combination inhibitors vitro. A increased benefit vitro vivo, outperforming either monotherapy. CONCLUSION Histone distributed regions regulate promote growth. Targeting therefore potential therapy