Washington, DC The National Cancer Institute has awarded a $4.37 million grant to Jeffrey A. Toretsky, MD, at Georgetown Lombardi Comprehensive Cancer Center, to advance a recent scientific laboratory discovery into a new treatment for Ewing's sarcoma. The grant, issued under the American Recovery and Reinvestment Act, will help fund preclinical toxicology studies of a new agent identified by Toretsky and his team a critical step in drug development that usually is stalled for years because of cost.
"A significant hindrance of therapeutic development is translation from the laboratory to the clinic," says Toretsky. "This funding not only allows this step to occur, but it could dramatically accelerate the time of taking our laboratory finding and turning it into a therapy for patients."
If preclinical toxicology studies are successful, a clinical trial with the agent would follow. The studies of the agent are based on a 2009 discovery in which Toretsky and his colleagues found 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. Toretsky described the finding in the journal Nature Medicine.
He and his colleagues discovered and successfully tested 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," says Toretsky.
Agents currently in use that work against fusion proteins inhibit a single protein to stop intrinsic enzymatic activity; one example is Gleevec, used for chronic myelogenous leukemia (CML). Torestsky believes his team's finding 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
In the United States, about 500 people are diagnosed each year with Ewing's sarcoma, and they are treated with a combination of five different chemotherapy drugs. Between 60 and 70 percent of patients survive over time, but with side effects from the treatment. Additional treatment options are available but without long-term potential for cure for patients whose cancer progresses, Toretsky says.
Discovery: A Long Journey
Torestky and his colleagues have chartered a 15-year path towards a new treatment for Ewing's sarcoma. Ewing's sarcoma is caused by the exchange of DNA between two chromosomes, a process known as a translocation. A new gene is created when the EWS gene on chromosome 22 fuses to the FLI1 gene on chromosome 11, and its product is the fusion protein EWS-FLI1 responsible for cancer formation. EWS-FLI1 is a good target for anticancer therapy since it is critical for the tumor and only present in tumor cells. It is a so-called disordered protein, which means it does not have a rigid structure. A number of cancer-causing proteins are disordered.
Previously, Toretsky and his colleagues were the first to make a recombinant EWS-FLI1 fusion protein. They used this recombinant protein to discover that the fusion protein stuck to another protein, RNA helicase A (RHA). RHA is a molecule that forms protein complexes in order to control gene transcription. "We believe that when RHA binds to EWS-FLI1, the combination becomes more powerful at turning genes on and off," says Hayriye Verda Erkizan, PhD, a postdoctoral researcher in Toretsky's lab.
Then, from a library of 3,000 small molecules loaned to Georgetown from the National Cancer Institute, the researchers searched for a small molecule that would bind on to EWS-FLI1. They found one, and further discovered the same molecule, NSC635437, could stop EWS-FLI1's fusion protein from sticking to RHA.
Erkizan described the finding as a wonderful discovery because the notion long accepted among scientists is that it is not possible to block protein-protein interactions given that the surface of many of these proteins are slippery and therefore drugs cannot bind to them.
The researchers tested the agent in laboratory cell culture, and with the help of GUMC's Drug Discovery Program, designed a stronger derivative compound they called YK-4-279. In this study, they tested YK-4-279 in two different animal models of Ewing's sarcoma and found that the agent significantly inhibited the growth of tumors. There was an 80% reduction in the growth of treated tumors compared to untreated tumors. These results serve as a proof of principle that inhibiting protein-protein interaction can work as a novel therapeutic that will target only cancer cells.
"We may be able to use this strategy to attack proteins we thought to be impervious to manipulation," he says.
Toretsky is an inventor on a patent application that has been filed by Georgetown University related to the technology described.
|Contact: Karen Mallet|
Georgetown University Medical Center