Presentation Time: 11:05-11:25
Home University: UNC-Chapel Hill
Research Mentor: Ian Davis, UNC School of Medicine
Program: SURF
Research Title: Exploring Synergistic Effects of Small Molecules in Ewing sarcoma
Ewing sarcoma, the second most common bone cancer in children and young adults, is driven by a chromosomal translocation that generates the critical fusion oncoprotein EWS-FLI11. EWS-FLI1 binds to specific genomic loci where it increases chromatin accessibility. EWS-FLI1 results in nucleosome depletion at targeted sites, and silencing EWS-FLI in cells results in decreased chromatin accessibility at EWS-FLI1 target sites. Previously, the Davis Lab demonstrated that small molecules can also decrease chromatin accessibility at EWS-FLI1 target sites (Pattenden et al). Furthermore, a small molecule modulator of EWS-FLI1 protein stability, 7ai, has been recently identified, but its effects on chromatin accessibility have not been as well characterized (Su et. al). As these compounds have different mechanisms of action, we asked whether synergy might be achieved by combining compounds with effects on chromatin accessibility . Using FAIRE-qPCR, I will characterize the effects of 7ai on chromatin accessibility at EWS-FLI1 target loci alone and in combination with UNC0621 and Varinostat, small molecules that decrease chromatin accessibility at these sites. As these compounds also have effects on Ewing sarcoma cell proliferation, I will use two proliferation assays, the WST assay and the real-time microscopy using the Incucyte to assess the effect of the compounds singly and in combination on the metabolic activity and proliferation of Ewing sarcoma cells, respectively. Ultimately, this drug discovery research not only aids to understand the mechanism of EWS-FLI1, but it also has the possibility to increase Ewing Sarcoma survival rates