P10.23.B UNCOVERING THERAPEUTIC VULNERABILITIES IN PEDIATRIC BCOR/L1-DRIVEN CNS TUMORS THROUGH MULTI-OMICS PROFILING

Abstract BACKGROUND BCOR and its homologue BCORL1 are core components of the non-canonical polycomb repressor complex (PRC) 1.1, playing a central role in epigenetic gene silencing and transcriptional repression. Genomic alterations involving BCOR/L1, primarily BCOR internal tandem duplications (ITD) or BCOR/L1 fusions, occur in central nervous system (CNS) tumors with distinct molecular characteristics and poor clinical outcome. Thus far, the impact of these BCOR/L1-alterations on PRC1.1 functionality in CNS tumors remains elusive. Therefore, a better understanding of the underlying biology is essential to develop improved therapies MATERIAL AND METHODS By analyzing bulk, single-cell RNA and chromatin immunoprecipitation (ChIP) sequencing data in tissue samples, we explored whether BCOR-ITD or BCOR/L1 fusions share molecular mechanisms and target gene activation patterns in brain tumors. The functionality and targetable vulnerabilities of identified BCOR/L1 targets were confirmed in-vitro and in-vivo using patient-derived and transgenic cell as well as xenograft models. RESULTS BCOR-altered CNS tumors harbor a unique transcriptomic gene signature, indicative of impaired PRC1.1 repressive functions. This dysregulation leads to activation of distinct BCOR-mediated (FGF/FGFR, PDGFR) and PRC1.1 target genes (GATA6). ChIP-Sequencing analyses confirmed recruitment of activating histone marks (H3K27ac), despite binding of KDM2B and mutant BCOR/L1 to the respective target loci. In parallel, PRC1/2-mediated repressive histone modifications, H3K27me3 and H2AK119ub, were absent. Single-cell RNA sequencing further uncovered a distinct tumor cell population enriched for GATA6 and FGF/FGFR expression. Finally, the dependency on receptor tyrosine kinase signaling activity, identified in BCOR/L1-altered tumors, was confirmed by drug screening, revealing FGFR/PDGFR inhibitors as highly active compounds. The multikinase inhibitor nintedanib not only showed anti-cancer activity in a BCORL1-fused PDX model, but also clinical activity in two patients affected by progressive BCOR/L1-driven CNS tumors. CONCLUSION We deciphered key oncogenic pathways driven by BCOR/BCORL1 alterations in CNS tumors and identified potential targeted therapeutics, which may be leveraged for improved therapy of patients suffering from these aggressive malignancies.