Funded Research
Read about the results of this study!
February 15, 2008: The Liddy Shriver Sarcoma Initiative and the Amschwand Sarcoma Cancer Foundation are co-funding a $50,000 research study, "Small-molecule targeting of EWS-FLI1," at the Lombardi Comprehensive Cancer Center at Georgetown University. The funding of this grant is also made possible by a generous gift from the Arlo and Susan Ellison family to the Liddy Shriver Sarcoma Initiative.
Led by Jeffrey A. Toretsky, M.D. who is in the Departments of Oncology and Pediatrics and is the Co-director of the Pediatric Cancer Research Program, and involving Milton L. Brown, M.D., Ph.D., who is the Director of the Drug Discovery Program at Georgetown University Medical School, this study acts as a cornerstone upon which to base molecular therapy directed towards disrupting the relationship between EWS-FLI1 and RNA Helicase A to improve patient survival. The following appears in the abstract of the grant application:
"The Ewing’s Sarcoma Family of Tumors (ESFT) contains a characteristic translocation, t(11:22), which leads to the oncogenic transcription factor EWS-FLI1. We sought to dissect EWS-FLI1 induced tumorigenesis by identifying its critical protein partners. We identified RNA Helicase A (RHA, a.k.a. NDHII), a DEAD/H family member that modulates gene expression, as a critical partner of EWS-FLI1. Our data suggest that complex formation between EWS-FLI1 and RHA augments EWS-FLI1-mediated transcription and transformation. When RHA is specifically mutated to prevent EWS-FLI1 binding, there is no augmentation of soft-agar colony formation. Expression of the E9R peptide, that prevents EWS-FLI1 binding to RHA, eliminates ESFT soft agar colony formation, while other non-ESFT tumors are unaffected. Together, these findings suggest that RNA helicases interact with tumor-specific oncoproteins, such as EWS-FLI1, to modulate transformation. Using surface plasmon resonance (Biacore) screening, we have identified a series of small molecules that bind to EWS-FLI1. One of these small molecules has a significant structural homology to the E9R peptide and is our current lead compound. Since we hypothesize that the interaction of RHA with EWS-FLI1 results in a potent ESFT oncogenic transcriptional activator/coactivator complex, our efforts are focused on developing optimized lead compounds that block RHA binding to EWS-FLI1."
You can read more about the approach they are taking in this study in Dr. Toretsky’s article, Small Molecules that can inhibit EWS-FL1 may represent novel and specific therapy for ESFT patients, which appears in the February 2008 issue of ESUN.