HG-15: TARGETING HISTONE MUTATIONS IN PEDIATRIC HIGH GRADE GLIOMAS

INTRODUCTION: Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPGs) are among the most lethal cancers known with no effective cure. Recently, somatic mutations in the H3F3A or HIST1H3B genes have been detected in the majority of midline high-grade pediatric glioma cases which leads to an amino acid change at lysine 27 of H3 to methionine. One viable option is to target genes that when inhibited selectively kill tumor cells expressing H3K27M mutant proteins. METHODS: We performed a genome-wide shRNA screen to identify genes that when depleted selectively kills cells with the H3K27M mutation. RESULTS: We identified two major signaling pathways that have not been previously reported as therapeutic targets for DIPG. We found that depletion or inhibition of these pathways selectively inhibit the proliferation of H3K27M mutant DIPG cells, decreases cell colony formation and increases apoptosis compared to WT expressing tumors. Additionally, clinically relevant inhibitors of these pathways, that is compounds that are either FDA approved or already in clinical testing, produced similar results. We also found proteins in these pathways that are overexpressed in brain tumors and cell lines with H3K27M mutations. CONCLUSION: Malignant gliomas including DIPG, are one of the most aggressive primary malignant brain tumors with no effective therapies at this time. We have found two signaling pathways that are important for this disease and identified clinically relevant drugs. These studies pave the way for developing molecularly targeted therapies as our understanding how these mutations lead to tumorigenesis unfold.