Desmoplastic Small Round Cell Tumors: Investigation of its Pathogenesis and Development of Novel Therapies
Desmoplastic small round cell tumor (DSRCT) is one of the most aggressive pediatric sarcomas with a low survival rates despite the combination of aggressive chemotherapy, surgery, and radiation therapy. No targeted treatments are currently available and little is known about the biology of this tumor type. Although all patients harbor a very specific chromosomal rearrangements that generates a novel fusion gene, how this gene induces the development of cancer remains a mystery. Without a deeper understanding of the molecular mechanism resulting in the development of DSRCT developing novel therapy remains extremely challenging. In the proposed work we will tackle this knowledge gap using a series of complementary approaches taking advantage of the unique expertise of our research group.
The goals of this grant proposal are to better understand the mechanisms underlying DSRCT formation and to develop novel therapeutic strategies. We will do this using through two complementary approaches. First, we propose to use an innovative genome engineering method that our lab as developed to create the first animal model of DSRCT. This model will be essential to better understand the molecular mechanism that cause DSRCT in humans, and will serve as a powerful preclinical platform to rapidly test novel therapeutic approaches. Second, taking advantage of the availability of tumors and tumor cell lines derived from DSCRT patients here at MSKCC, we will perform CRISPR screens to identify and validate novel therapeutic targets. Successful completion of these studies will transform our understanding of DSCRT biology, will provide the first mouse model of this rare and lethal tumor, and may result in the identification of novel therapeutic strategies that can be rapidly translated into the clinic.