Project 2

Pancreatic cancer is highly aggressive and has an extremely low 5-year survival rate. Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to the majority of treatments including cytotoxic chemotherapy, targeted agents, and immuno-therapy. Treatment resistance has been linked to tumor heterogeneity, limited tissue penetration of drugs, and an immunosuppressive tumor microenvironment (TME). PIN1 is a cis-trans prolyl isomerase that controls proline-mediated phosphorylation signaling events that is overexpressed both in pancreatic cancer cells and cancer-associated fibroblasts. PIN1 overexpression is a major contributor to tumorigenesis, activating several oncoproteins, including proteins in the KRAS pathway,17 and simultaneously inactivating several tumor suppressors. PIN1 promotes an immunosuppressive/treatment-resistant TME, by up-regulating PD-L1 (programmed cell-death receptor-1). Guided by our resources and preliminary data, we propose a collaboration between University of California, Riverside (UCR) and City of Hope Comprehensive Cancer Center (CoHCCC) to optimize and develop a potent and selective PIN1 inhibitor for treatment of pancreatic cancer. Aim 1 will design, synthesize, and iteratively optimize novel, drug-like PIN1 targeting agents. Aim 2 will study the mechanism of action and efficacy of the most promising agents in cellular and animal models of pancreatic cancer. We will assess the pharmacokinetic properties of refined agents in mice and test their efficacy in animal models of pancreatic cancer.