Targeting eNOS in Pancreatic Cancer

Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS or NOS III) has been implicated recently in the pathogenesis of PDAC. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDAC. Genetic deficiency in eNOS limited the development of pre-invasive pancreatic lesions and trended towards an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor L-NAME. Similarly, other transgenic models of oncogenic KRas-driven tumors responded to L-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which L-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose L-NAME for clinical investigations in treatment of PDAC and possibly other KRas-driven human cancers.