Grant: Project Grant

Synovial sarcoma is a cancer that most commonly afflicts adolescents and young adults who should have a long life ahead of them. Surgery and radiotherapy cure some patients, but unfortunately a lack of effective drug treatments mean that less than half of patients survive more than 10 years after diagnosis. This situation is frustrating because we do know what causes this form of cancer: a single DNA mutation that generates a mutant protein called SS18SSX. Most other types of cancer harbour multiple DNA mutations, but mouse model studies from our group have proven that this single mutation is enough on its own to generate synovial sarcomas. So, how can one single mutation cause all the changes to cell biology to make a cancer happen? The answer appears to be epigenetics - the SS18SSX mutant protein makes massive changes to how DNA is organized in a way that activates cell growth programs, causing cells to divide uncontrollably and become cancerous. Our recent research applying new technologies to a large series of surgically-excised tumors from Canadian patients has identified an unusual, disease-specific pattern of epigenetic changes in synovial sarcoma that affects the activity of DNA segments called enhancers that control gene expression. We propose to use newly developed tools to prove that these changes are driven by SS18SSX and to test if they can be reversed with emerging epigenetic drugs. We are uniquely positioned to do so, by (1) having access to what is currently the world's most comprehensive epigenomic dataset on synovial sarcoma, (2) having developed a genetically-engineered mouse model that recapitulates human disease and can be used to test drugs and confirm they counteract SS18SSX, and (3) through leadership roles in the International Rare Cancer Initiative that provide a route to translate findings into clinical trials that will help young people with synovial sarcoma.