Functional Analysis and Therapeutic Targeting of STAG2 Mutations in Ewing sarcoma
Ewing sarcoma is an aggressive, sometimes lethal pediatric bone cancer. Though rare, it is the subject of much research because once the tumor recurs or spreads, it is difficult to treat successfully. Ewing sarcoma, like other cancers, is a genetic disease caused by changes in the genetic code of the cancer cells that are not present in the patient's normal tissues. Much of modern cancer research is focused on identifying genetic changes in different cancers, since identifying them is a key step towards understanding the cancer and therefore developing rational approaches to treat it. It has long been known that Ewing sarcoma occurs when a piece of one gene (named "EWS") is inappropriately attached to a piece of another gene (named "FLI"). However, it has proven very challenging to identify strategies to attack this EWS-FLI "translocation" with new medicines. Therefore, over the past several years, researchers have attempted to identify other genetic changes in Ewing sarcoma, with the hope that they might shed additional light on the cause of the cancer and provide targets for developing new drugs.
In 2011 we identified a new Ewing sarcoma gene called "STAG2," and recent research by ourselves and others has shown that STAG2 is the most common genetic change in Ewing sarcoma other than the defining EWS-FLI translocation. In this grant application we propose several inter-related projects designed to understand how mutations in STAG2 cause Ewing sarcoma, and to attempt to identify ways to target this mutant gene with new therapies.