Jeffrey A Toretsky

Title

Professor
Molecular Oncology Program Co-leader

Department

Lombardi Comprehensive Cancer Center (LCCC)
Research

Research

Dr. Jeffrey Toretsky has been studying Ewings sarcoma since 1992. His early work investigated minimal residual disease, antisense oligonucleotide growth inhibition, and novel EWS-FLI1 targets and protein interactions. The Toretsky laboratory continues to focus on Ewings sarcoma, since the tumors contain a unique target, EWS-FLI1, which is not found in non-tumor cells. This unique target offers an opportunity to create new medicines that will more specifically eliminate tumor growth while sparing normal cells. In addition to being a unique cancer target, EWS-FLI1 has the biochemical properties of an intrinsically disordered protein (IDP).

Direct screening for small molecules that bind to EWS-FLI1 required recombinant protein along with surface plasmon resonance technology. Once a lead compound was identified, a network of collaborators in medicinal chemistry, biochemistry, structural biology, and pharmacology helped advance the molecule YK-4-279, as an inhibitor of EWS-FLI1, towards a clinical trial. Significant efforts failed to obtain a commercial partner to license YK-4-279 due to the extraordinarily rare incidence of Ewings sarcoma. Therefore, in 2010 Dr. Toretsky founded TDP Biotechnology, LLC. TDP obtained an exclusive license for the commercial development of YK-4-279 and in 2012 the patent for the composition of matter was issued by the USPTO to Georgetown University.

The oncologic process set in motion by EWS-FLI1 remains relatively cryptic despite the identification of many transcriptional targets. There are two additional projects underway in the Toretsky laboratory that are elucidating the mechanisms of EWS-FLI1 oncogenesis. The Toretsky laboratory identified RNA Helicase A (RHA) as a partner of EWS-FLI1 in 2006, thus the effects of EWS-FLI1 upon RHA function as a helicase is a current topic of research. In addition, a more comprehensive evaluation of EWS-FLI1 partner proteins and nuclear structures is also providing novel insights into function.

Dr. Toretsky is currently expanding his research by considering paradigms that allow targeting other cancers where critical Achilles’ heel proteins share IDP properties. IDPs contain motifs that lack fixed canonical structure and are poorly visualized in current structural technologies. There is a thermodynamic advantage that allows binding of small molecules to these flexible motifs; thus, disruption of key protein-protein interactions is both possible and ultimately druggable. An active area of research in Dr. Toretsky’s laboratory is both gaining insight through additional specific IDPs, such as the synovial sarcoma protein SSX-SS18, and theoretical modeling.

Dr. Toretsky continues to practice as a pediatric hematologist/oncologist by co-directing a multidisciplinary sarcoma clinic at Children’s National Medical Center along with regular inpatient attending. In addition to Ewings sarcoma, his clinical interests include osteosarcoma (bone cancer), synovial sarcoma, rhabdomyosarcoma, and many other related tumors. He hopes to prescribe more effective and precisely targeted therapies for his patients in the future.