Characterizing and targeting SWI/SNF chromatin remodeling activity in Ewing sarcoma
Ewing sarcoma is an aggressive bone cancer that mostly affects children and teenagers. This cancer is usually caused by a genetic accident that fuses two genes, EWSR1 and FLI1, creating a new "fusion" gene called EWS-FLI1. This fusion gene acts like a faulty switch, turning on many other genes that drive the cancer's growth and make it hard to treat. Current treatments for Ewing sarcoma—like chemotherapy and surgery—are not very specific and often don't work well for patients whose cancer has spread. In our lab, we are looking for better, more targeted ways to treat this disease. We found that the EWS-FLI1 fusion protein works together with the SWI/SNF complex to control critical parts of the DNA, driving cancer growth. Excitingly, new drugs that target the SWI/SNF complex are now available, including first-in-class compounds developed by our group, and we want to understand the chromatin and transcriptional features that determine which tumors respond best to these drugs.
Project Goals
The goal of this research is to study the chromatin and transcriptional features of response to SWI/SNF inhibition in Ewing sarcoma. We suspect that understanding how the cell's DNA organization and gene activity change in response to these drugs will reveal why some tumors are more aggressive and harder to treat. We have new drugs that can block the SWI/SNF complex—a group of proteins that help control how DNA is used in the cell. Notably, SWI/SNF inhibitory drugs are also being tested in clinical trials in human patients and can be taken orally. We will test these drugs in laboratory animal models to find out if this approach could work as a new treatment and to identify biomarkers that help predict which patients are most likely to respond. We hope to start a small clinical trial in the future where we give SWI/SNF drugs to Ewing sarcoma patients, using these biomarkers to guide treatment decisions. This will lead to more personalized and effective care for young children with this lethal disease.
