Desmoplastic Small Round Cell Tumor: Establishment and Validation of New Cell Lines and Therapeutic Targeting of the EWS-WT1 Transcription Factor using Splice Switching Oligonucleotides

Desmoplastic small round cell tumor (DSRCT) is an aggressive primitive sarcoma of adolescents and young adults. The hallmark and key genetic driver of DSRCT is the EWS-WT1 gene fusion, which encodes an oncogenic chimeric transcription factor. Although EWS-WT1 represents the ideal therapeutic target in DSRCT, direct targeting of transcription factors has so far proved elusive with conventional drugs. Furthermore pre-clinical studies to identify and develop new therapies have been hampered by the paucity of available DSRCT cell line.

This proposal aims to tackle these issues by developing the first molecular targeted therapy for DSRCT based upon an innovative approach of using next-generation highly biostable, splice-switching oligonucleotides (SSO) to target the EWS-WT1 pre-mRNA. We propose a systematic pre-clinical effort to test this approach taking advantage of our newly established, fusion positive DSRCT cell lines. We will use these novel cell lines and the sole publicly available DSRCT line (JN-DSRCT-1) to validate this strategy, which if effective, will have broad implications for sarcomas driven by oncogenic fusion transcription factors.