Jeffrey A. Toretsky, MD
The major focus of my laboratory is to evaluate the role of chromosomal breakpoint-generated fusion proteins upon oncogenesis and tumor maintenance. My laboratory focuses on the Ewing’s Sarcoma Family of Tumors (ESFT), which contain pathognomonic EWS-ets fusion proteins. These fusion proteins are the ideal therapeutic targets as they exist only in ESFT cells and their elimination in laboratory models is toxic to the tumors. My laboratory is currently investigating three areas of ESFT biology: (1) the role of insulin-like growth factor type 1 (IGF-I) in patients with ESFT, (2) the role of the protein tyrosine phosphatase L1 (PTPL1) as a significant transcriptional target of EWS-FLI1, the most common EWS-ets protein, and (3) the requirement of RNA helicase A (RHA) as a cofactor of EWS-FLI1 function. In order to take advantage of the uniqueness of EWS-FLI1 as a therapeutic target, my laboratory identifies protein partners of EWS-FLI1. The interaction points between these protein partners and EWS-FLI1 have the potential to be unique in three-dimensional space. These unique interaction points could then be targets for EWS-FLI1 inactivation. Our current work utilizes surface plasmon resonance to identify small molecules that bind to EWS-FLI1, medicinal chemistry to optimize binding, and a series of bioassays to evaluate the effect of small molecules upon EWS-FLI1 and ESFT cells. Ultimately, I want to apply our discoveries to create novel therapies that would reduce morbidity and improve the survival of patients with ESFT and other sarcomas.