P12.51.B INTEGRATIVE MULTIOMIC ANALYSIS IDENTIFIES EIF4A1 AND CDK9 AS KEY THERAPEUTIC TARGETS IN OLIGODENDROGLIOMAS

Abstract BACKGROUND Oligodendroglioma, IDH-mutant and 1p/19q co-deleted are rare adult brain tumors. Although their prognosis is better than that of other adult-type diffuse gliomas, it remains heterogeneous with most cases being incurable and a significant proportion of patients having a poor outcome despite surgery, radiotherapy and chemotherapy. To better characterize oligodendrogliomas heterogeneity and explore new therapeutic strategies, we took advantage of the POLA network and assembled the largest cohort known to date for multiomic profiling. MATERIAL AND METHODS We assembled a large multiomic cohort of 117 low grade gliomas (86 oligodendrogliomas, 16 Glioblastomas and 15 Astrocytomas) including genome, transcriptome, proteome and phosphoproteome layers as well as clinical information. RESULTS Unsupervised multiomic integration identified three robust subgroups of oligodendrogliomas with different molecular profiles associated with different histo-molecular characteristics and clinical outcomes. We identified a subgroup exhibiting an oligodendrocyte precursor cell-like profile, enriched in cell cycle, MYC target features and associated with a worse outcome. Integrative mechanistic analysis revealed a prominent role for translation, MYC and CDK Kinase family in this subgroup, unraveled at proteome and phosphoproteome levels. Importantly, we validated the therapeutic potential of Eukaryotic Translation Initiation Factor 4A1 (EIF4A) and CDK9 inhibition using relevant patient-derived cellular and in vivo models. CONCLUSION Our multiomic study provides a comprehensive molecular and clinical landscape of oligodendrogliomas and reveals that targeting the regulation of transcription and translation initiation could improve the prognosis of oligodendroglioma. CDK9 and EIF4A inhibitors, currently evaluated in clinical trials for other cancers, represent attractive new therapeutic targets for aggressive oligodendrogliomas.