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GUMC discovery highlights new direction for drug discovery
Date:7/5/2009

Washington, DC In a discovery that rebuffs conventional scientific thinking, researchers at Georgetown University Medical Center (GUMC) have discovered a novel way to block the activity of the fusion protein responsible for Ewing's sarcoma, a rare cancer found in children and young adults.

In the paper published online July 5 in Nature Medicine, they report discovering and successfully testing a small molecule that keeps the fusion protein from sticking to another protein that is critical for tumor formation. The researchers say this interaction is unique and is especially surprising since the Ewing's sarcoma fusion protein is extremely flexible, which allows it to change shape constantly.

"Most targeted small molecule cancer drugs inhibit the intrinsic activity of a single protein, but our agent stops two proteins from interacting. This has never been shown before with a cancer-causing fusion protein and represents a potentially novel medical therapy in the future," says the study's lead investigator, Jeffrey Toretsky, MD, a pediatric oncology physician and researcher at GUMC's Lombardi Comprehensive Cancer Center.

The study could provide a model upon which to design treatment for other disorders caused by the interaction between two proteins, and may be especially useful in cancers caused by translocations of genes, such as sarcomas and leukemias, the researchers say. Agents in use now that work against fusion proteins inhibit a single protein to stop intrinsic enzymatic activity; one example is Gleevec, used for chronic myelogenous leukemia (CML). The Ewing's sarcoma fusion protein, known as EWS-FLI1, lacks enzymatic activity, "and this difference is why our work is significant," Toretsky says.

In the United States, about 500 patients annually are diagnosed with the cancer, and they are treated with a combination of five different chemotherapy drugs. Between 60-70 percent of patients survive over time, but with
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Contact: Karen Mallet
km463@georgetown.edu
215-514-9751
Georgetown University Medical Center
Source:Eurekalert

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