ID #623 Modelling CNS tumors with BCOR alterations for understanding biology and therapy development
Francesco Bernaudo, Chantal Giebel, Phylicia Stathi, Álvaro Regaño, Federico Aniello, Vijay Ramaswamy, Katharina Bruckner, Daniela Loetsch-Gojo, Mariëtte Kranendonk, Jens Bunt, Katja von Hoff, Johannes Gojo, Marcel KoolAbstract
Central nervous system tumors with BCOR alterations (CNS-BCOR) represent a recently discovered brain tumor type. DNA methylation data and transcriptome analyses revealed two distinct but highly related subtypes, carrying either an internal tandem duplication (ITD) in exon 15 of BCOR (BCOR-ITD) or gene fusions of BCOR/BCORL1 with different partners, most commonly EP300 and CREBBP (BCOR-FUS). Historically, CNS-BCOR tumors were histologically diagnosed as various other brain tumor types, resulting in heterogenous treatments and lack of specific standardized treatment protocols. Although overall survival remains poor, retrospective analyses indicated benefit from radiotherapy, while chemotherapeutic response appeared restricted to BCOR-ITD tumors.
Transcriptomic analyses showed that BCOR-ITD tumors exhibit less differentiated, stem cell-like signatures, enriched in neurodevelopmental pathways, while BCOR-FUS showed enrichment for neuronal-glia differentiation pathways. Both subtypes shared deregulation of development and proliferative programs relative to normal brain tissues. Pathways (NOTCH, HIPPO, TGFB) and genes relevant to tumor development and potential druggable targets (PDGFRA, EGFR, FGFR3, IGF1R) have been identified. Furthermore, as few preclinical CNS-BCOR models are available, we aim to establish human models to investigate tumor biology, including patient-derived lines and xenografts, and genetically engineered brain tumor organoids (GEBTOs). GEBTOs were generated from human stem cell-derived forebrain and cerebellar organoids engineered to express BCOR-ITD or BCOR-FUS constructs, allowing assessment of BCOR-driven oncogenic potential on developing brain cells on transcriptomic and proteomic levels. The analyses allow GEBTOs comparison to patient-derived lines and primary tumors. Transcriptomically-identified targets are under validation at RNA and protein levels, and targeted drug screening approaches focusing on pathway-specific inhibition and candidate therapeutic targets are being conducted on patient-derived BCOR-ITD (n = 2) and BCOR-FUS (n = 3) lines.
In conclusion, integrating molecular profiling, preclinical modeling, and functional analyses aims to elucidate BCOR-driven tumorigenesis and identify effective therapies for CNS-BCOR patients.