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, “This makes LSD-1 an important target for the development of new drugs to treat Ewing sarcoma.”
Dr. Lessnick explained, “For 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.”
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.
“We 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,” Sharma said.
“After 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,” Sharma said. “Our tests in Ewing sarcoma tissue cultures show they are extremely potent.”
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, “We think it may play a larger role in Ewing sarcoma than simply turning off a handful of genes, and we’re looking into that.”
This study was published in Oncogene (2012; doi:10.1038/onc.2012.525).