Abstract 639: Prevention of pancreatitis and subsequent pancreatic cancer and fibrosis development by PI3Kγ inhibition

Abstract Anti-inflammatory, immunosuppressive macrophages play significant roles in promoting both tumorigenesis and fibrosis. Wound-healing type macrophages accumulate in sites of tissue injury, such as the cirrhotic liver, where they can induce oxidative damage and secrete immunosuppressive and pro-fibrotic factors that lead to oncogenesis. These innate immune cells are also major cellular producers of PDGFB and TGF-β1, which stimulate fibroblasts to secrete extracellular matrix proteins, such as collagen, and which also promote metastatic progression of neoplastic diseases. Chronic liver and pancreatic inflammation are significant risk factors for the development of hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC), respectively. We have determined that the myeloid cell specific PI3K isoform PI3Kγ promotes the accumulation of myeloid cells and their immune suppressive polarization within the tumor microenvironment (TME), and that this kinase thereby promotes tumor growth in animal models of cancer, including PDAC. Genetic and pharmacological inhibition of PI3Kγ suppresses tumor growth and reduces fibrosis that is associated with PDAC and other tumors. Targeting immune suppressive myeloid cells represent an emerging approach within the field of cancer immunotherapy and fibrosis treatment; indeed, inhibition of PI3Kγ by the therapeutic eganelisib has shown beneficial effects, including increased overall and progression-free survival in clinical trials for melanoma, head and neck carcinoma, urothelial carcinoma and triple negative breast carcinoma. In this project, we are exploringWe examined the effect of whether PI3Kγ inhibition can in cancer prevention using mouse models of prevent cancer development by suppressing damaging chronic hepatic and pancreatic inflammation, associated fibrosis, and progression towards tumorigenesis using models of HCC and PDAC. We found that PI3Kγ inhibition prevented prevents acute and chronic inflammation and that promotes normal tissue loss and development of fibrosis in mouse models of chronic pancreatitis and liver inflammation. Studies are underway to determine iOur studies indicate thatf PI3Kγ inhibition can also prevent the development of pancreatic and liver carcinoma that results fromin response to chronic inflammation and fibrosis. Our These studies thus far suggest the a potential role of for PI3Kγ inhibition in the prevention of cancer development by preventing the chronic inflammation that leads towards fibrosis and carcinogenesis. The results of these studies could be applied to the future design of clinical trials with using clinical PI3Kγ inhibitors. Citation Format: Anghesom Ghebremedhin, Judith Varner, Marc Paradise. Prevention of pancreatitis and subsequent pancreatic cancer and fibrosis development by PI3Kγ inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 639.