Desmoplastic small round cell tumor: from genomics to targets, potential paths to future therapeutics.

Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive pediatric cancer caused by a reciprocal translocation between chromosomes 11 and 22, leading to the formation of the EWSR1::WT1 oncoprotein. DSRCT presents most commonly in the abdominal and pelvic peritoneum and remains refractory to current treatment regimens which include chemotherapy, radiotherapy, and surgery. As a rare cancer, sample and model availability have been a limiting factor to DSRCT research. However, the establishment of rare tumor banks and novel cell lines have recently propelled critical advances in the understanding of DSRCT biology and the identification of potentially promising targeted therapeutics. Here we review model and dataset availability, current understanding of the EWSR1::WT1 oncogenic mechanism, and promising preclinical therapeutics, some of which are now advancing to clinical trials. We discuss efforts to inhibit critical dependencies including NTRK3, EGFR, and CDK4/6 as well as novel immunotherapy strategies targeting surface markers highly expressed in DSRCT such as B7-H3 or neopeptides either derived from or driven by the fusion oncoprotein. Finally, we discuss the prospect of combination therapies and strategies for prioritizing clinical translation.

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Copyright © 2024 Magrath, Espinosa-Cotton, Flinchum, Sampath, Cheung and Lee.

Déclaration de conflit d'intérêts

Both Memorial Sloan Kettering Cancer Center and NKC have financial interest in Y-mAbs and Eureka Therapeutics. NKC reports receiving past commercial research grants from Y-mAbs Therapeutics. NKC was named as inventor on multiple patents filed by Memorial Sloan Kettering Cancer Center, including those licensed to Ymabs Therapeutics and Biotec Pharmacon. Y-mAbs Therapeutics, Eureka Therapeutics and Biotec Pharmacon were not involved in the study design, collection, analysis, interpretation of data, the writing of this manuscript or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.