Scientific Objective and Rationale: Pancreatic cancer is an extremely aggressive disease and is projected to become the second leading cause of cancer-related death in the United States by 2020. Metastatic pancreatic cancer is one of the main reasons for dire statistics. Recent studies have shown that immune cells play a major role in contributing to tumor growth and metastasis. Therefore, it is critical to determine how immune cells play a part in promoting metastasis and what would be the therapeutic implications of interrupting their function. This research project builds on preliminary findings suggesting that reduced levels of immune cytokine IL-23 correlate with pro-metastatic potential of pancreatic cancer in patients and mouse models. Here, we will use both patient data and mouse models that recapitulate metastatic pancreatic cancer to understand: (1) how IL-23 contributes to metastatic potential of pancreatic cancer; (2) which IL-23-producing immune or stromal cells are important in this process; and (3) how do the levels of IL-23 contribute to patient survival and metastatic outcomes in pancreatic cancer.

Career Goals in Cancer Research: Pancreatic cancer is a devastating disease. Having my uncle wither away and die within weeks of receiving his diagnosis of pancreatic cancer has contributed to my passion for finding its cure. Ever since starting my work on pancreatic cancer, I have believed that novel and effective immune-based approaches could make a transformative impact on the survival of pancreatic cancer patients. A Department of Defense Peer Reviewed Cancer Research Program career development award will have a great impact on achieving my career goal, which is to head a laboratory that investigates mechanisms central to the establishment of a pro-tumorigenic microenvironment in pancreatic adenocarcinoma and translate these research findings into novel, clinically feasible treatment modalities. Throughout my career, I have been carefully assembling academic and research skill sets that would make this ambition possible. My predoctoral training experiences gave me cross-disciplinary instruction in cell biology and mouse models of cancer biology that, in combination with my postdoctoral training in tumor immunology, will allow me to successfully pursue the didactic and research goals proposed in this application. I believe that there is a multifaceted role for immunity in cancer initiation and hypothesize that cancers actively modulate immune responses to enable metastatic progression of the disease. These are fundamental topics in cancer immunology that I am uniquely suited to address in the coming years and in the context of this award application. This award will provide me with the necessary time and support at a key juncture in my career. This include opportunities for collaborations with senior investigators in the field, as well as time and resources to amass preliminary data for application for R01 funding.

Applicability of the Research: Our ability to develop targeted therapies against pancreatic cancer is heavily dependent on a more detailed understanding of the molecular mechanisms of pancreatic carcinogenesis through generation and examination of accurate model systems. The propensity of PDAC cells to metastasize is a major cause of death and an impediment to successful therapy. Current methods of diagnosing PDAC cannot reliably predict metastatic propensity of PDAC in any given patient, highlighting the need to identify novel mechanisms of potentially measurable and targetable pro-metastatic switches. Our proposed studies will investigate a novel mechanism of metastatic ability in pancreatic cancer. We anticipate gaining critical mechanistic insights into function of IL-23 in PDAC as well as the therapeutic potential of IL-23 in preventing or regressing metastasis. Identification and characterization of unique IL-23-related mechanisms may elucidate novel targetable signaling pathways that lead to metastatic propensity of PDAC.

Benefit to active duty Service members, Veterans, and other military beneficiaries. The proposed work can potentially have a significant impact on military beneficiaries because of (1) cigarette smoking, which accounts for 30% of active-duty personnel, is a significant risk factor for pancreatic cancer; (2) occupational exposure to chemicals, such as asbestos, benzene, and others significantly increases the risk of pancreatic cancer; (3) radiation is a well-known risk factor for pancreatic cancer. Veterans that were exposed to ionizing radiation, including military service in Japan during World War II and atmospheric nuclear weapon testing between 1945 and 1962, are associated with increased risk of diagnosis with pancreatic cancer; (4) new onset diabetes, which can lead to or be a sign of pancreatic cancer, has high rates among military personnel; and (5) Pancreatic cancer, has a dismal 8 percent 5-year survival rate, and is currently ranked as a third leading cause of cancer-related death, disproportionately affects Veterans and their family members. Therefore, the proposed research will directly address the immediate need for understanding and treating pancreatic cancer.