Investigating the non-cell autonomous immune effects of mutant p53 in pancreatic cancer

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Project Summary/Abstract The prognosis for pancreatic cancer patients is unequivocally poor. This is due in part to the fibrotic and immunosuppressive microenvironment of pancreatic tumors, which serves as a physical barrier to chemotherapy and immunotherapy. Intratumoral genetic alterations can cause remodeling of the immune environment through distinct cellular mechanisms. Oncogenic Kras gene mutations are the most frequently occurring genetic event in pancreatic cancer, followed by transforming alterations in TP53. Using both mouse models and human samples, we will characterize the changes in the immune cell composition of pancreatic tumors with specific p53 mutations. My proposal will delineate the underlying cellular mechanism of p53- dependent immune cell recruitment to the tumor microenvironment in the context of pancreatic cancer. In addition, we will investigate the potential of mutant p53 to serve as a marker of resistance to immunotherapy. This proposal could support changing clinical practice as integrated analysis of tumor genetic makeup and immune profiles may be used to develop precision immunotherapy. Building on my background in molecular genetics, I plan to study the relationship between intra-tumoral gene alterations and the immune system. I will need training in pancreatic cancer, immunology and cell biology and have decided to study under the mentorship of Dr. Dafna Bar-Sagi and Dr. George Miller. Dr. Bar-Sagi, an international expert in oncogenic Ras and cell biology, has trained over 50 individuals at the graduate and post-graduate level over her 30 years in academia and has authored over 150 peer-reviewed manuscripts. Dr. Miller, leader of NYU Perlmutter Cancer Center’s Tumor Immunology Program, is a well published immunologist whose research has formed the basis for four separate clinical trials in pancreatic cancer. Over the course of my training, I will develop expertise in pancreatic cancer and immunological techniques and principles, receive mentorship in professional development and collaborate with academic leaders. My career plan consists of laboratory training, regular meetings with my mentor and co-mentor, active conference participation and formal didactic coursework. My advisory committee will help me attain my goal of becoming an independent physician scientist and leader in pancreatic cancer research. Dr. Diane Simeone, Director of the NYU Pancreatic Cancer Center and world-renowned surgeon scientist, will provide valuable guidance on pancreatic cancer and Dr. Paul Oberstein, chair of our Gastrointestinal Medical Oncology Group, will help place my studies in a translational context. Dr. Kwok-Kin Wong, Director of the Division of Hematology and Oncology, is a successful clinician scientist with a well published laboratory that studies clinical therapeutics using pre-clinical models. NYU Langone Health has robust scientific and clinical programs dedicated to pancreatic cancer, making it a world leader. I will benefit from interacting with the many prominent faculty with clinical and/or basic science research experience, professional development programs and world class facilities.