Abstract 6131: Development of a transgenic porcine model of pancreatic adenocarcinoma

Abstract

Abstract Introduction Five-year survival from pancreatic cancer (PC) is less than 10% and has not changed substantially in decades. Current murine models may not adequately mimic human PC which may contribute to the lack of progress in survival. We attempted PC induction in transgenic swine with the goal of creating a more clinically-relevant model. Methods Transgenic Oncopigs (n=8, male, 5 mo; wt 37.2 kg, nsrrc.missouri.edu; somatic LSL cassette TP53R167H and KRASG12D) were injected via laparotomy with AdCre (1010 vp/uL) ± IL-8 (5 ng/mL; for adenoviral entry into epithelia and local inflammation) into the main pancreatic duct (MPD; via duodenotomy) or duct to the isolated pancreatic connecting lobe (CL). Wildtype (WT) control pigs (n=6, male, 5mo; wt 45kg UNL Mead) were also injected via laparotomy with either normal saline (NS), AdCre, or AdCre + IL-8 (5ng/mL) into the CL. Subjects were necropsied after ≤10 wk, followed by histology (Table 1.) Experimental design showing intervention. MPD-Main Pancreatic Duct, CL-Connecting Lobe, NS-NaCLSwineMPDCLNSAdCreIL-8Necropsy DayOutcomeOCM1+--++17Died prematurely2+--++73Reached endpoint3-+-++12Euthanized due to illness4-+-++14Euthanized due to illness5-+-++14Euthanized due to illness6-+-+-59Euthanized electively7-+-++22Euthanized due to illness8-+-++35Euthanized electivelyWT9-++--35Reached endpoint10-+-+-35Reached endpoint11-++--33Reached endpoint12-+-+-36Reached endpoint13-+-++28Reached endpoint14-+-++28Reached endpoint Results Subject Oncopig 1 died prematurely from gastric perforation (tissue NA); subjects Oncopigs 3, 4, 5, 7 were euthanized early due to illness (manifested as decreased feeding, decreased stooling, abdominal distension). Necropsy revealed fulminant hemorrhagic pancreatitis which resulted in gastric outlet obstruction. Subject Oncopig 7 also was noted to have peritoneal carcinomatosis. Subjects Oncopigs 2, 6, 8 were clinically well at euthanasia. Subjects Oncopigs 2, 6, 8 did not have any tumor on H&E, but did have pancreatic ductal hyperplasia. Subjects Oncopigs 3, 4, 5, and 7 had widespread microscopic evidence of epithelial tumor on H&E. IHC of the tumor regions for mutant p53, mutant KRAS, CD31, CD45, CD46, CD68, Pankeratin, and CK-19 demonstrated transgene expression and was consistent with an adenocarcinoma of gastrointestinal/pancreaticobiliary origin. Areas of inflammation were positive for macrophage and lymphocyte markers. The Wildtype WT pigs were clinically normal at ~4 weeks; necropsy showed no gross evidence of pancreatitis. H&E performed on tissue showed no tumor. Conclusion This study demonstrated that PC can be induced in the transgenic Oncopig, which has inducible expression of activated KRAS and inactive p53 under control of a floxed stop codon. However, induced Oncopigs will need to live longer to yield a usable PC model. Addition of IL-8 may have contributed to the severe pancreatitis and early mortality. Future studies will focus on modulation of pancreatitis and tumor spread, with optimization of the survival period. Citation Format: Neesha S. Patel, Katie Bailey, Audrey Lazenby, Mark A. Carlson. Development of a transgenic porcine model of pancreatic adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6131.