Abstract A078: Inhibition of precancerous transformation via drug-induced p53 activation

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the US and has a 5-year survival rate of less than 10%. This low survival rate is largely due to low rates of early detection and the lack of treatments capable of inhibiting disease progression. Risk factors for PDAC include smoking, alcohol abuse, and pancreatitis. Pancreatic injury associated with pancreatitis is characterized by inflammation, fibrosis, and acinar cell death. Surviving acinar cells undergo acinar-to-ductal metaplasia (ADM), a regenerative process in which cells dedifferentiate, proliferate, and then redifferentiate into acinar cells. Recurrent pancreatic injury can sustain ADM and preclude redifferentiation, resulting in exocrine insufficiency and the formation of precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). PanIN lesions harbor activating mutations in the MAP kinase pathway protein Kras, and can transform into PDAC after acquiring inactivating mutations in tumor suppressor p53. The lack of treatment options for pancreatitis patients reinforces the need for strategies that could resolve pancreatic damage and stop disease progression. Towards this end, we have recently shown that drug-induced activation of p53 in mouse models of pancreatitis preserves acinar cells, reduces the proliferation of PanIN lesions, and lowers levels of MAP kinase phosphorylation. We have also observed p53 activation during embryonic development of the pancreas, specifically in exocrine progenitor cells that commit to the acinar fate, suggesting a novel role of p53 in pancreatic differentiation. Based on our findings, we hypothesize that p53 activation can signal for the differentiation of acinar cells, and restrain PanIN proliferation through the suppression of MAP kinase signaling. Our studies will define the role of p53 in pancreatic differentiation and the potential of pharmacological p53 activation for the treatment for pancreatitis and prevention of PDAC. Citation Format: Jennifer J. Twardowski, Thomas I. Heist, Stephano S. Mello. Inhibition of precancerous transformation via drug-induced p53 activation [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A078.