Functional Screening and Transcriptomic Analysis Identify Novel Druggable Dependencies and Immunotherapy Targets in Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a rare, primitive sarcoma most commonly found in the abdominal and pelvic cavities. DSRCT is characterized by a chromosomal translocation that leads to the formation of the EWSR1::WT1 fusion oncogene, which alters gene expression and drives oncogenesis. With the exception of this translocation, few other recurrent mutations have been identified making it challenging to develop targeted therapies. Given this low rate of recurrent mutations, we hypothesize that examining the DSRCT transcriptome may be more successful in identifying novel therapies. However, only limited transcriptomic analysis has been performed on primary DSRCT samples, none with associated outcomes data. Here we report the results of our effort to better characterize DSRCT using RNA-seq on more than 50 tumor samples. We identify pathways and genes not only enriched in DSRCT but associated with poor DSRCT prognosis and which may have important therapeutic implications. We further identify novel immunotherapy targets expressed on the surface of DSRCT and which have a greater specificity for DSRCT than current targets under investigation. Overall design: RNA was islated from a set of 57 DSRCT tumors and 5 normal tissues with two replicates per sample