Abstract 2069: Therapeutic targeting of ependymoma as informed by oncogenic enhancers

Abstract

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas commonly resist chemotherapy and lack available targeted agents for clinical trial development. In the case of genomically balanced ependymomas, and those driven by fusion oncoproteins, we hypothesized that the chromatin landscapes could uncover oncogenes that would inform actionable targets for therapy and reveal specific transcriptional circuitries to identify molecular origins of the disease. We therefore interrogated the oncogenic drivers of ependymoma by characterizing the active regulatory landscapes of 42 primary tumors through an integrative analysis of H3K27ac ChIP-seq, RNA-seq, whole-exome sequencing (WES), whole genome sequencing (WGS), copy number profiling, and DNA methylation profiling. Across the landscape of ependymal tumors, enhancer mapping revealed putative oncogenes, including NFIX, MIRLET7BHG, FGFR1, WEE1, and MTSS1L, and delineated subgroup specific enhancer lesions. Reconstruction of enhancer networks permitted the identification of core transcription factors (TFs) that establish ependymoma cell state, and lineage-specifying TFs that dictate molecular subgroup identity. Lineage-associated TFs point to distinct spatio-temporal origins of ependymoma subgroups such as FOXJ1 TF activity and expression observed preferentially in subsets of hindbrain ependymomas. To translate our results into a potential clinical paradigm, we demonstrate cancer dependencies on super enhancer associated genes and lineage TFs, and establish the utility of chromatin landscape analysis to predict novel targets for cancer therapy. Citation Format: Stephen C. Mack, Global Ependymoma Network of Excellence. Therapeutic targeting of ependymoma as informed by oncogenic enhancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2069.