Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options that has a five-year survival rate of <10%. PDAC progression is associated with dysregulated tumor and whole- body metabolism that impacts therapy and quality of life, which has motivated research on how to best exploit metabolic dependencies in PDAC for better cancer treatment. Nutrient utilization by cancer cells is regulated in part by the availability of metabolites in the environment, and the PDAC tumor microenvironment in particular is highly desmoplastic, consisting of stromal cells, extracellular matrix, and nutrient-poor interstitial fluid. These microenvironmental factors can impact therapy response, suggesting that the efficacies of metabolism-targeted drugs can be improved by manipulating components of the PDAC tumor microenvironment. One determinant of metabolite levels in the tumor microenvironment is diet, and how diet affects cancer progression and treatment is an important question for many patients. Since dietary recommendations to patients must be made in the context of therapies being received, the value of any dietary intervention likely lies in its ability to enhance tumor responses to cancer therapies. Understanding the molecular mechanisms that drive synergistic interactions between diet and cancer therapies is critical for the translation of dietary recommendations into patient care. The main objective of this proposal is to identify dietary interventions that synergize with cancer therapies to impair PDAC progression. Mouse PDAC models will be used to examine how different diets enhance the efficacies of standard-of-care FOLFIRINOX chemotherapy (Aim 1), lipid metabolism inhibitors in development for cancer treatment (Aim 2), and inducers of ferroptosis, a non-apoptotic form of cell death being explored for PDAC treatment (Aim 3). Mass spectrometry-based metabolomics and lipidomics, stable isotope nutrient tracing, and RNA sequencing will be used to determine how diet-mediated changes to nutrient levels in the tumor microenvironment alter the metabolism of PDAC tumors to shape their responses to these therapies. Elucidating the metabolic mechanisms that underlie synergistic diet-drug combinations will provide scientific evidence that can benefit patients with guidance on how to best incorporate diet and nutrition into cancer therapy. The proposed training plan will help me transition into an independent academic position. A team of outstanding scientists will mentor me to help me achieve this goal: Dr. Tyler Jacks, a leader in mouse cancer models; Dr. Omer Yilmaz, a leader in dietary effects on cancer progression; Dr. Caroline Lewis, a leader in mass spectrometry-based metabolomics and lipidomics technologies; and Dr. Brian Wolpin, a leader in PDAC epidemiology. My training plan also outlines activities that will help me cultivate mentors, improve my scientific skillset, improve science communic...