CDLD Pilot Project 3: Targeting HSP70 for the Treatment of Pancreatic Cance

Tim Barnoud – Department of Biochemistry

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Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer-related deaths in the United States. Despite the emergence of new targeted therapies for PDAC, most patients remain refractory to treatment. As a result, the 5-year survival of patients with PDAC remains at a dismal 10%, with survival rates even lower for patients with metastatic PDAC. Taken together, there is an urgent and unmet clinical need for the discovery of novel therapies for PDAC in order to impact the lives of the nearly 50,000 patients that succumb to the disease every year. Evidence from several groups points to the molecular chaperone HSP70 as playing an important role in the initiation and progression of PDAC; subsequently, HSP70 inhibitors have emerged as a potential therapeutic strategy for the treatment of PDAC. We have recently developed a specific HSP70 inhibitor, AP-4-139B, that binds and inhibits the stress induced HSP70 but does not bind to other family members required for life. This inhibitor is broadly cytotoxic to numerous tumor cell lines, including human and murine PDAC cells. We have shown that this inhibitor has potent activity in tumor cells while being markedly less toxic to non-transformed cells. In xenograft models, our HSP70 inhibitor shows efficacy as a single agent without evidence of toxicity in mice and synergizes with other FDA-approved therapies, including MAPK pathway inhibitors targeting B-RAF and MEK. Lastly, our published and preliminary data suggest that HSP70 inhibition induces markers of immunogenic cell death, supporting the premise that HSP70 may impact the response to immunotherapy. We hypothesize that HSP70 may be an attractive and novel therapeutic target for the treatment of PDAC. The long-term goal of our proposed research is to use our novel HSP70 inhibitor for the treatment of xenograft, allograft, and metastatic mouse models of PDAC. A secondary goal of this application is to determine the impact of HSP70 inhibition on the immunogenic response in PDAC. We have engaged a strong team with expertise in pancreatic cancer (John O’Bryan) and immuno-oncology (Shikhar Mehrotra).