Desmoplastic small round cell tumor: validation and further development of novel active compounds emerging from high-throughput chemical screens and establishment of xenografts for preclinical studies
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive tumor of adolescents and young adults characterized by the chromosomal translocation t(11:22)(p13;q12) that generates a novel, chimeric transcription factor EWS-WT1. DSRCT has a dismal prognosis in the setting of current treatment options. The first Aim of this project is to better define the cellular pathways targeted by 5 compounds that we have recently identified as potent inhibitors of DSRCT cell growth in a large-scale chemical screen by using m1croarray-based gene expression analysis to generate compound-specific signatures. This work should, firstly, help us prioritize compounds for further pre-clinical drug development; secondly, it may highlight the sensitivity of DSRCT cells to inhibition of a specific cellular pathway for which there are existing, FDA-approved drugs. Finally, understanding the cellular pathways inhibited by the top 5 most active compounds may provide new insights into the special biology of DSRCT. The chemical screening approach described here has been validated by other members of our laboratory in the development of novel agents in other tumor types such as Ewing’s sarcoma and lung cancer. The second Aim is to establish new DSRCT xenograft and cell line models for pre-clinical testing of these compounds. There is currently only one DSRCT cell line available and so all pre-clinical investigations have been limited. We will attempt to generate DSRCT xenografts through an established protocol in our antitumor assessment core facility and from xenograft tissue, we will attempt to derive additional DSRCT cell lines. This would significantly extend our capabilities for experimentation and allow for pre-clinical testing of the compounds of interest from Aim 1. The impact of this work will also be broad, because we plan to share with the sarcoma research community any new xenograft and cell line models to facilitate other pre-clinical studies in DSRCT.