What we do
Targeting the Achilles Heel of Ewing Sarcoma
Our lab focuses on Ewing sarcoma, since the tumors contain a unique target that 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 2009, Dr. Toretsky and his team revealed the molecule called YK-4-279 that targets Ewing sarcoma with an article in Nature Medicine. YK-4-279 has the potential to be a potent new strategy in the fight against not only Ewing sarcoma, but also other cancers and diseases with similar characteristics.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 2014 Dr. Toretsky cofounded Tokalas, Inc. to advance an analog of YK-4-279 to a clinical trial that is commencing in the spring of 2016.
The emerging role of the spliceosome in Ewing Sarcoma
Alternative splicing has been implicated as an oncogenic process and provides both a categorization of cancer as well as an opportunity for more effective targeted treatments. Spliceosomal network interactions, including proteins that recognize splice enhancer and silencer regions, are critical for the regulation of alternative splicing leading to oncogenic protein isoforms. Interrogation of complete protein networks remains challenging because it is difficult to modify single interactions while preserving overall network architecture. We hypothesized that EWS-FLI1, Ewing sarcoma (ES) oncoprotein, modulates post-transcriptional gene regulation through novel protein interactions. EWS-FLI1 has multiple connections to the spliceosome and reduction of EWS-FLI1 alters significant numbers of exon skipping and intron inclusion events identified from RNA-seq. Assessment of aberrant splicing driven by EWS-FLI1 may inform oncogenesis and reciprocally, EWS-FLI1 activities may inform splicing mechanisms.
Liquid-liquid phase separation
A deeper investigation into the mechanism of YK-4-279 has led Dr. Toretsky into the world of phase separation and soft matter. He is particularly interested in understanding how phase-separated protein complexes occur and how they function in RNA processing. Small molecules may be useful in disrupting local biochemistry to prevent or induce phase separation