Abstract 1102: Model optimization and chemoprevention of IPMN driven PDAC in KPSD4 mouse model
Authors: Kumar Gaurav , Madka Venkateshwar , Singh Anil , Kumar Nandini , Stratton Nicole , Lightfoot Stanley , Mohammed Altaf , Miller Mark S. , Rao Chinthalapally V. 
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with one of the lowest five-year survival rates. Patients with intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms (MCNs) are at high risk for the development of PDAC and thus are target populations for intervention with chemopreventive agents. The lack of optimized animal models of IPMNs has limited the development of chemopreventive agents and vaccines. We have thus characterized the suitability of the Pdx1Cre.LSL-KrasG12D.SMAD4flox/flox (KPSD4) model for IPMN formation and their progression to PDAC. In addition, as a proof-of-principle we assessed the chemopreventive efficacy of gefitinib in the KPSD4 model. The development of IPMNs and PDAC were monitored up to 44 weeks of age by serial sacrifice at 6, 12, 18, 24, 36, and 44 weeks of age in male and female KPSD4 mice (n=6/time point), at which time the pancreata were analyzed for lesion development.

The KPSD4 mouse model developed both IPMNs and pancreatic intraepithelial neoplasia (PanINs) spontaneously. IPMNs were histologically classified as i) independent (single IPMN duct); ii) IPMN cluster/adenoma (multiple IPMN ducts as cluster or adenoma); iii) IPMN borderline (dysplasia with or without CIS); and iv) IPMN invasive carcinoma. At 6 weeks of age, the pancreata were normal in appearance (&gt;94% in male; &gt;97% female) with low frequency (Mean ± SEM) of PanINs (Male, 6.5±2.65; Female, 3.44±2.12) and IPMNs (Male, 5.5±2.21; Female, 2.56±0.96). At 12 weeks of age, there was a significant increase of IPMN number and their progression to borderline type that advanced to carcinoma by age 24 weeks. At 36 weeks of age, &gt;80% of the KPSD4 mice developed carcinomas that rapidly spread to the entire pancreas by 44 weeks of age. Overall, IPMN progression to PDAC required somewhat less time than did the progression of PanINs to PDAC in the KPSD4 mouse model. A major limitation of the KPSD4 model was the mortality due to secondary phenotypes. In KPSD4 mice, ~40% mortality was observed between 6 and 18 weeks of age due to intestinal tumors leading to obstruction.

For the chemopreventive efficacy bioassay, 6 week old male and female KPSD4 mice (34/group) were fed diets containing 0 or 100 ppm of gefitinib for 18 weeks. Mice were euthanized at 24 weeks of age and pancreata were assessed for IPMNs, PanINs, and PDAC. Control-diet-fed male and female mice showed IPMN driven PDAC incidences of 83% and 100%, respectively, whereas male and female KPSD4 mice exposed to 100 ppm gefitinib showed PDAC incidences of 50% and 27% (p&lt;0.0006), respectively. A significant reduction of IPMN individual ducts, adenoma, and IPMN borderline was observed in KPSD4 mice fed gefitinib, thus demonstrating a strong suppression of IPMN individual duct progression to more advanced lesions upon treatment with gefitinib. [Supported by NCI HHSN261201500038I].

Citation Format: Gaurav Kumar, Venkateshwar Madka, Anil Singh, Nandini Kumar, Nicole Stratton, Stanley Lightfoot, Altaf Mohammed, Mark S. Miller, Chinthalapally V. Rao. Model optimization and chemoprevention of IPMN driven PDAC in KPSD4 mouse model [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 1102.