Abstract 13: Aspirin and metformin combination inhibits PDAC progression and metastasis in KPC mice
Authors: Altaf Mohammed, Venkateshwar Madka, Gaurav Kumar, Anil Singh, Nicole Stratton, Stanley Lightfoot, Mark S. Miller, Chinthalapally V. Rao
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that generally escapes detection until it reaches an advanced stage. Hence, developing strategies that inhibit PDAC progression is of utmost importance. Observational studies suggest that frequent use of metformin and aspirin reduces PDAC risk. Since these agents have different mechanisms of action, combining them may lead to additive inhibitory effects on PDAC. Here we aimed to validate the usefulness of the combination of aspirin with metformin in the Ptf1acre-ERTM.LSL-KrasG12D/+. LSL-Trp53R172H/+ (KPC) mouse model. Aspirin (600 ppm or 1,200 ppm) and metformin (500 ppm or 1,000 ppm) either individually or in combination were tested for their effect on pancreatic intraepithelial neoplasia (PanINs), PDAC, and metastasis in KPC mice. Eight week-old KPC mice were administered tamoxifen by gavage to initiate tumorigenesis (PanINs) and randomized to control and experimental groups. Seven weeks later, experimental diets containing test agents individually or in combination were administered to the KPC mice. Mice were euthanized 32 weeks post-tamoxifen administration and pancreata were evaluated. Histological analysis showed 100% penetrance of PanIN lesions in all the KPC mice. Control diet fed mice showed 100% PDAC incidence. Aspirin (1,200 ppm) or metformin (1,000 ppm) showed significant inhibition of PDAC incidence by 15.6% (P&amp;lt;0.03) and 23.5%(P&amp;lt;0.0007), respectively, while the combination of aspirin (600 ppm or 1,200 ppm) with metformin (1,000 ppm) also showed significant 20% (P&amp;lt;0.02) to 23% (P&amp;lt;0.02) inhibition of PDAC incidence. Metastasis incidence was observed in 69% KPC mice fed the control diet. Importantly, KPC mice fed 1,000 ppm metformin showed only 21% metastasis incidence (P&amp;lt;0.002). Also, combination of aspirin (600 ppm or 1,200 ppm) with metformin (500 ppm or 1000 ppm) inhibited metastasis by 40% - 56% (P&amp;lt;0.07-P&amp;lt;0.007). Tumor necrosis was observed in 61% of control mice that was also significantly reduced by 73% - 100% (P&amp;lt;0.004 - P&amp;lt;0.0001) in treated mice. There was also an inhibition of PanINs by aspirin (43.8%; p&amp;lt;0.02) or metformin (35.7%; P&amp;lt;0.034) alone when compared with control mice. Biomarker analysis suggested that treatment with aspirin and/or metformin showed a significant inhibition of PCNA index (P&amp;lt;0.05- P&amp;lt;0.0001). In spite of aggressive tumor progression in KPC mice, aspirin and/or metformin showed inhibitory effects on PDAC incidence, metastasis, and necrosis; however, combinations failed to show any additive or synergistic effect when compared with 1,000 ppm metformin alone treatment. (Supported by NCI PREVENT Program HHSN261201200013I/ HHSN26100010) Citation Format: Altaf Mohammed, Venkateshwar Madka, Gaurav Kumar, Anil Singh, Nicole Stratton, Stanley Lightfoot, Mark S. Miller, Chinthalapally V. Rao. Aspirin and metformin combination inhibits PDAC progression and metastasis in KPC mice [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 13.