Development of Combination Therapies for Desmoplastic Small Round Cell Tumor (DSRCT)
Mentor: Patrick Grohar
Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy that is most commonly diagnosed in adolescent and young adult males. The patients are frequently metastatic at diagnosis and the overall prognosis is poor. There is currently no accepted standard treatment for this disease and despite aggressive chemotherapy, surgery, radiation therapy, and stem cell transplant, the 5-year survival is less than 15%. Therefore, there is a need for new therapies for this disease.
Our lab has recently shown that DSRCT depends on the activity of the EWS-WT1 transcription factor for cell survival. Blocking the activity of this protein leads to tumor cell death. We have identified a compound, lurbinectedin, which inhibits EWS-WT1 leading to cell death in vitro and a decrease in tumor size in xenograft mouse models. The goal of this study is to identify compounds that work with lurbinectedin to further reduce cell viability.
In this project, we will screen a library of every FDA approved compound to identify synergistic combinations that work with lurbinectedin to inhibit DSRCT cell growth. We will compare the activity of these combinations to others identified using a pathway-based candidate small molecule approach. The most promising combinations will be further studied in vitro and in animal models of DSRCT. The goal will be to translate the top combination to the clinic.
We have a promising candidate combination therapy and therefore will be screening for compounds complementary or superior to this candidate.
