Abstract IA015: Comprehensive in vivo phenotyping of fusion-driven pediatric sarcomas

Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma that has molecular features of immature skeletal muscle. The most aggressive forms of rhabdomyosarcoma are driven by two genes that are inappropriately juxtaposed to form a fusion-oncogene. These fusion-oncogenes consists of transcription factors, various chromatin regulators, and kinases that obtain gain-of-function activities. Fusion-positive rhabdomyosarcomas have no targeted therapies. Patients are treated general chemotherapy, surgery, and radiation and survivors of childhood cancer have an increased risk of adverse health impacts, secondary cancers, and premature death. There is a critical need to delineate the biology of fusion-driven pediatric rhabdomyosarcoma and leverage this biology into therapeutic opportunities. This has been challenging to investigate given the lack of animal models, cell lines, and patient-derived xenograft models, and is the motivation and rationale for our research. Through a collaborative effort with clinical sequencing of patient tumors by the NCI-COG-NCH Molecular Characterization Initiative, we have developed new personalized medicine zebrafish models of fusion-driven rhabdomyosarcomas. We have used our established fusion-oncogene modeling pipeline to incorporate a subset of pediatric RMS fusion-oncogenes into the zebrafish genome and assess their oncogenic potential and molecular features. This pipeline generates zebrafish tumors that recapitulate the human disease by integrating the human fusion-oncogene into the zebrafish genome with a transposase-based system. By modeling multiple fusion-oncogenes in vivo, we can elucidate shared biology and therapeutic vulnerabilities, including how fusion-oncogenes interface and misappropriate developmental pathways. Moreover, these studies can uncover putative tumor origins by overlaying transcriptional and chromatin accessibility profiles with developmental cell states. Currently, our group is focused on fusions with similar partners and domains for targeted therapeutic approaches that are likely applicable across a subset of rare cancers. More broadly, this modeling strategy could be implemented to identify potential shared dependencies across rhabdomyosarcoma subtypes or sarcoma in general. Citation Format: Genevieve Kendall. Comprehensive in vivo phenotyping of fusion-driven pediatric sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr IA015.