PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is now the 3rd leading cause of cancer related death in the United States. The overwhelming majority of patients receive systemic chemotherapy as part of a neoadjuvant, adjuvant, or palliative treatment regimen. These systemic agents do not provide durable survival benefits in patients with PDAC. The reason for this is unknown and given that there are no promising new agents on the horizon, novel strategies to increase treatment responsiveness or identify preventative measures are desperately needed. Our group and others have reported the importance of the host microbiome on PDAC development and progression. The microbiome is the milieu of microorganisms that share the body space of every individual and has been increasingly associated with a variety of human diseases, including pancreatic cancer. Building on prior published work and provocative preliminary data from our lab, we propose novel experiments that will identify bacteria as modulators of NK cells and their anti-tumor function in order to augment response to chemotherapy and provide a preventative and treatment strategy. Our innovative approach utilizing gnotobiotic technology, microbial manipulation, and the innate immune system to enhance PDAC responsiveness to chemotherapy has not been undertaken previously and will advance the field of pancreatic cancer research. We hypothesize that selective intestinal bacteria can delay or prevent PDAC development and furthermore, enhance the anti-tumor efficacy of gemcitabine and 5-FU, common chemotherapeutic agents used to treat PDAC. In order to test this hypothesis, we propose the following specific aims: Aim 1: Establish the ability of E. hirae to prevent PDAC development utilizing a xenograft and genetic mouse model of pancreatic cancer. Aim 2: Establish the impact of E. hirae to augment chemotherapy efficacy in PDAC. With fulfillment of the Specific Aims, this proposal will confirm the role of Enterococcus hirae to enhance the anti-PDAC role of NK cells in PDAC prevention as well as its response to chemotherapy treatment. Such knowledge will advance our understanding of host factors that impact the responsiveness of PDAC to chemotherapy and provide transformative data to support a National Institutes of Health R01 application and first-in-human trials for bacterial manipulation with E. hirae that targets the anti-PDAC role of NK cells as a preventative and treatment strategy.

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer related death in the United States, partly due to the lack of preventative and effective chemotherapeutic strategies. Research from our group and others implicates the microbiota, the commensal, symbiotic, and pathobiont milieu of bacteria and other microorganisms that share the body space of every individual, in PDAC progression. This novel application, which builds on provocative preliminary data, seeks to identify bacteria that potentiate the anti-tumor response of the innate immune system as a preventative strategy and to enhance the response of PDAC to currently used systemic chemotherapeutic agents.