Possible new treatment for Ewing sarcoma
Discovery of a new drug with high potential to treat Ewing sarcoma and of the previously unknown mechanism behind the disease came hand-in-hand. Lysine specific demethylase (LSD-1), an enzyme, was found to turn off gene expression in Ewing sarcoma by interacting with EWS/FLI, which is a protein that almost always causes Ewing sarcoma.
Ewing sarcoma is an often deadly cancer of children and young adults. By turning off specific genes, the complex of EWS/FLI-LSD1 causes the development of Ewing sarcoma. Stephen Lessnick, MD, PhD, of Huntsman Cancer Institute at the University of Utah, said, â€śThis makes LSD-1 an important target for the development of new drugs to treat Ewing sarcoma.â€ť
Dr. Lessnick explained, â€śFor a long time, we've known that EWS/FLI works by binding to DNA and turning on genes that activate cancer formation. It was a surprise to find out that it turns genes off as well. The beauty, if there's anything beautiful about a nasty disease like this, is that if we can inhibit EWS/FLI, we can inhibit this cancer, because EWS/FLI is the master regulator of Ewing sarcoma.â€ť
While Lessnick and his colleagues worked on EWS/FLI in their basic science lab, Sunil Sharma, MD, also at the Huntsman Cancer Institute, had already focused on LSD-1 as a possible target for new cancer treatments. He had been working for several years on designing drugs that would inhibit its actions.
â€śWe had found that LSD-1 was important for regulation of a variety of properties in several different cancers, including acute leukemias, breast and prostate cancers,â€ť Sharma said.
â€śAfter Steve showed that LSD-1 was directly regulating the function of EWS/FLI, we teamed up with him to see whether the LSD inhibitors we had discovered worked in Ewing sarcoma models,â€ť Sharma said. â€śOur tests in Ewing sarcoma tissue cultures show they are extremely potent.â€ť
Lessnick and Sharma are now collaborating to further test LSD inhibitors in animal models as they work toward approval of a first-in-man clinical trial. Also, Lessnick is continuing basic science research on LSD-1 in Ewing sarcoma. He explained, â€śWe think it may play a larger role in Ewing sarcoma than simply turning off a handful of genes, and we're looking into that.â€ťThis study was published in Oncogene (2012; doi:10.1038/onc.2012.525).