TASK ORDER: PRECLINICAL TESTING OF CD73 INHIBITORS FOR PANCREATIC CANCER IMMUNOPREVENTION

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Pancreatic cancer (PC) is a highly aggressive cancer usually diagnosed at an advanced stage and has the worst prognosis of any cancer. Almost 57,600 individuals will be diagnosed with PC, with ~47,050 deaths expected, in the US alone in 2020. Although PC accounts for only about 3% of all cancers in the US, it accounts for about 7% of all cancer deaths. Moreover, recent incidence and mortality rates suggest an increasing trend of PC. Lack of effective early interventions are major factors contributing to the poor prognosis and dismal survival rates of PC patients. Despite many advances in the molecular genetics of human pancreatic cancers, targeted therapies have not yet translated to improved overall survival. Recent developments demonstrate that pre-invasive precursors, such as pancreatic intraepithelial neoplasia (PanINs), intrapapillary mucinous neoplasms (IPMNs), and cystadenomas, progress slowly over many years before developing into invasive PC. Yachida et al. has estimated that there is a window of opportunity of ~10 years from the moment a pancreatic epithelial cell gets an oncogenic hit to the time of diagnosis, which can be exploited to implement early intervention strategies. Hence, developing cancer prevention and interception strategies such as immunoprevention that delay/inhibit/prevent the formation and/or progression of pre-invasive lesions to PC is of utmost importance as if successful, it offers enormous potential for increasing the survival and lowering the societal financial burden. The adenosine signaling pathway, especially in the context of increased extracellular adenosine, is an important driver of tumor progression. Adenosine signaling is a mechanism that cells utilize to reduce inflammation in inflammatory and hypoxic environments. 5′-nucleotidase, also known as ecto-5′-nucleotidase or CD73, an enzyme that in humans encoded by the NT5E gene converts extracellular adenosine monophosphate (AMP) into immunosuppressive adenosine, which shuts down anti-tumor immune surveillance. Adenosine signals via adenosine receptors to promote immune suppression. There are four subtypes of adenosine receptors (A1A, A2A, A2B and A3AR), all of which are G protein coupled receptors (GPCR) and can be co-expressed on stromal and epithelial cells (10). CD73 can also be expressed on effector T cells. Emerging data in a number of solid tumors including PC demonstrates that CD73 overexpressed on neoplastic epithelium generates extracellular adenosine from AMP, which inhibits T cell and NK cell cytotoxicity, enabling tumor growth and disease progression. The importance of CD73 in PC growth is well established. These immunosuppressive and tumor promoting functions of CD73 make it an appealing target for prevention and treatment of pancreatic cancer. There are several clinical trials testing CD73-targeting agents, including small molecule CD73 inhibitors and anti-CD73 monoclonal antibody, based on the rationale that inhibition of CD73 activity may enhance anti-tumor immune surveillance at the level of T cells and other immune cells regulated by adenosine thereby delaying PC development. The overall goal of the project is to evaluate immunopreventive effects of clinically relevant small molecule CD73 inhibitors in pancreatic cancer syngraft and genetically engineered mouse models that recapitulate human pancreatic cancer progression.