Project summary/Abstract Pancreatic adenocarcinoma (PDAC) is an almost uniformly fatal disease that is most commonly diagnosed after the development of metastases. The tumor suppressor gene, p53, is the most commonly altered gene in human cancer and has been recognized as a genetic driver of PDAC in up to 75% of patients with direct roles in metastasis. While the effects of p53 mutations within cancer cells continue to be studied, the effects of such driver mutations on constituents of the tumor microenvironment (TME), and how these contribute to metastasis, remain limited. The ultimate goal of my work is to therapeutically exploit targets that arise in PDAC tumor cells and in the TME as a consequence of p53 mutation and the associated loss of p53-mediated tumor suppression. To this end, the Principal Investigator will utilize PDAC genetically engineered mouse models (GEMMs) and derived model systems to identify genes that partner with mutant p53 to generate invasive phenotypes and to determine genes that are synthetic lethal to mutant p53. The enclosed K08 award application is a comprehensive research, training, and career development plan designed to provide the Principal Investigator with the skill sets and expertise to establish an independent pancreatic cancer research program. As a fully trained surgical oncologist, the Principal Investigator possesses a unique clinical perspective of pancreatic cancer that may be leveraged with additional research training to contribute knowledge and therapeutic options to the field. Under the mentorship of Dr. Gigi Lozano, an international expert in p53 regulation and mutant p53 gain-of-function, the Principal Investigator will be immersed in a stimulating research environment at MD Anderson Cancer Center that will enable the completion of the research strategy. In parallel, the Principal Investigator will fulfill all training and career development goals through formal coursework and scheduled meetings with his mentor, advisors, and collaborators. To oversee the execution of the research strategy and the development of the Principal Investigator's expertise, an external advisory committee comprised of prominent scientists has been assembled, each with expertise that overlaps with the Principal Investigator's fields of study. Dr. Nancy Jenkins, a senior scientist and member of the National Academy of Sciences, has extensive experience with mouse models of cancer including specific experience in defining drivers of pancreatic cancer metastasis in transgenic mice. Dr. Michelle Barton, Dean of the Graduate School of Biomedical Sciences at MD Anderson and a NIH-funded Investigator, has rich experience in p53 biology, epigenetics, and mouse models of cancer. Both advisors have decades of experience educating and preparing trainees for the rigors of establishing independent research programs. Collectively, over the course of the 5-year K08 award period, the PI will utilize the environment, resources, and mentorship available at MD Anderson Cancer Center to launch a career in a new field of investigation as an independent Investigator.

PUBLIC HEALTH STATEMENT Approximately half of all human cancers exhibit alterations in the p53 tumor suppressor gene, most of which result in the survival, proliferation, and metastasis of tumor cells. Our studies will examine how mutations in the p53 gene support pancreatic tumor cell survival and metastasis through changes in gene expression and physical modifications to the tumor microenvironment. Through advances in our understanding of mutant p53 function, we hope to identify new vulnerabilities that may be therapeutically exploited to kill or limit the spread of pancreatic cancer cells.