Identification of novel drug targets and predictors of clinical outcomes in desmoplastic small round cell tumors using next-generation sequencing

Desmoplastic small round cell tumor (DSRCT) is a rare, highly-aggressive soft-tissue sarcoma with an overall five-year survival rate of less than 30%. Next generation sequencing (NGS) has given cancer researchers unprecedented access to the cancer genome, revealing targetable mutations, predictors of treatment response, and deepening our understanding of the genetic underpinnings of tumor development and progression. However, no large-scale genomic analysis of DSRCT has ever been performed, likely partially due to the difficulty in obtaining large numbers of primary tumor samples and partially due to lack of funding for such a rare disease. Because Memorial Sloan Kettering Cancer Center (MSK) is a tertiary referral hospital for pediatric malignancies and sarcomas, we have been able to collect upwards of 200 DSRCT tumor specimens from over 100 individual patients including long-term clinical follow-up information. We believe this likely represents the single largest collection of DSRCT specimens at any institution. Partnering with MSK’s Integrative Genomics Operation and Bioinformatics Core, we propose to use RNA-seq to sequence a pilot group of 80 DSRCT tumors, generating a robust, publicly-available dataset that can be used DSRCT researchers around the world. Our group will use this dataset to identify novel targets for immunotherapeutic, radioimmunotherapeutic, and targeted therapy strategies. Novel treatment strategies are desperately needed in DSRCT, as patients are treated with chemotherapy, surgery, and radiation and despite this aggressive approach relapse is common and almost invariably fatal. In addition to identifying novel drug targets, we will use this dataset to identify genetic predictors of clinical outcomes, including progression-free survival, overall survival, and response to chemotherapy. The combined experience of the Cheung lab in developing immunotherapy and radioimmunotherapy treatments for pediatric solid tumors and the Lee lab in dissecting the molecular mechanisms of DSRCT make this collaboration well-suited to conduct a project at the intersection of target discovery and genomic characterization. This discovery-based project will provide a genomic dataset that will serve as a resource for the DSRCT research community and has the potential to dramatically improve treatment of DSRCT through the identification of novel drug targets.