DIPG-40. HYPOXIC STRESS EXPOSES EPIGENETIC TARGETS TO ENHANCE RADIOTHERAPY RESPONSE IN H3K27M-POSITIVE PEDIATRIC DIFFUSE MIDLINE GLIOMAS

Abstract Diffuse midline gliomas (DMGs) are the most challenging to treat pediatric high-grade gliomas, with a dismal prognosis of 9 15 months median survival. The ones localized in pons not accessible surgery and rely on radiotherapy treatment. majority DMGs confer mutation histone 3 variants (H3.3 or H3.1), leading lysine 27 methionine substitution (H3K27M) consequent global decrease H3K27 trimethylation (H3K27me3), increased acetylation (H3K27ac) oncogenic changes gene expression. An intrinsic feature solid tumors, including DMGs, is occurrence hypoxic (low oxygenated) regions, which interferes efficiency radiotherapy. Identifying vulnerabilities hypoxia-exposed tumor cells might bring new approaches radiosensitizing DMG tumors. Hypoxia increases methylation multiple tumors but consequences hypoxia-induced hypermethylation H3K27M bearing unknown. Using syngeneic patient-derived cell lines, we show that presence prevents H3K27me3, also impairs hypoacetylation histones H3 H4 normally caused by stress. We enhancing conditions deacetylase (HDAC) inhibitors has stronger sensitization effect expressing than wild-type cells. While HDAC have been shown problematic due high systemic toxicity, our data points out inhibition context hypoxia may improve therapeutic efficacy. Recent studies showed possibility targeting hypoxia-activated pro-drugs, panobinostat. Our support such approach be an option target eliminate radiotherapy-resistant fraction, while minimizing toxicity all-time active inhibitors. Studies were supported grant UMO-2019/33/B/NZ1/01556 (KL) from National Science Center (Poland).