Alexandros Tzatsos MD PhD

Overview

Pancreatic cancer is the fourth most common cause of cancer related deaths in the United States with a 5-year survival rate less than 10%. Due to early metastatic spreading only a small percentage of patients benefit from surgical resection of the tumor and even then, the overall prognosis remains dismal. In patients that do not qualify for surgery, chemotherapy has marginally improved overall survival and frequently associates with severe adverse effects. Thus, there is an unmet need to identify molecular vulnerabilities and stratify pancreatic cancer patients based on the likelihood to respond to tailored treatments. In addition to genetic alterations, epigenetic mechanisms are also central to the development of pancreatic cancer and contribute in shaping the immunosuppressive tumor microenvironment that hinders the therapeutic effect of immune checkpoint inhibitors in reinvigorating cytotoxic T cells to fight cancer. By using genetically engineered mice we discovered that squamous-like tumors, a subtype of pancreatic cancer affecting about 20% of patients, is driven by deregulation of epigenetic mechanisms that delimit enhancer chromatin causing loss of cell identity and establishment of a highly desmoplastic and immunosuppressive tumor microenvironment. We also found that this subtype is selectively sensitive to Bromodomain and Extra-Terminal (BET) domain inhibitors that not only restricted tumor growth but also resolved desmoplasia in vivo uncovering an Achilles’ heel for patient-tailored therapies