Targeting ATRX mutation in UPS
| Undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive and difficult-to-treat forms of soft tissue sarcoma. It can occur almost anywhere in the body, often in the muscles or connective tissues, and tends to spread quickly to the lungs and other organs. Unlike many other sarcomas, UPS does not resemble any normal tissue. Because of this, it is often diagnosed by ruling out other types of sarcomas rather than by its own defining features. This lack of a clear identity has made it very difficult to understand how UPS begins and why it behaves so aggressively. UPS is often associated with poor clinical outcome because of its rapid growth, tendency to spread, and resistance to therapy. No effective targeted therapy has been developed for UPS patients, and their long-term survival remains poor despite surgery, chemotherapy, and radiation. Recent genomic profiling of human sarcomas has identified major genetic alterations for UPS. Among them, ATRX is altered in about one-third of UPS patients. ATRX functions to maintain the proper packing of DNA in human cells. It plays important roles in normal development and has been found to be mutated in many cancer types. However, how does ATRX mutations contribute to tumor development and how tumors with ATRX mutations can be treated remain largely unknown. These knowledge gaps further highlight the urgent need of relevant models to understand the mechanisms of ATRX function and identify targeting strategies. To address this, we have built new animal model that mimic the key genetic alterations of human UPS, including the loss of ATRX. Our novel model not only recapitulates the pathological feature of human UPS, but also reproduces the molecular features of human disease, giving us a powerful tool for discovering disease mechanism and identify therapeutic strategies. Using these tools, we have revealed novel functions of ATRX in regulating cell development and growth. More importantly, we identified pathways that are specifically required for the growth of tumor cells lack functional ATRX and thus can serve as therapeutic target. Built upon our findings, this proposal will utilize our unique animal model and newly established patient-derived models to further decipher the molecular mechanisms underlying ATRX function in tumor cells and, more importantly, evaluate novel therapy strategies that can be readily translated into clinical trials for UPS patients with ATRX mutations. Since ATRX is mutated in several sarcoma types, the impact of our proposal will go beyond the scope of UPS and eventually benefit different types of sarcoma patients. |