Abstract 1928: Identification of interleukin 13 receptor alpha 2 (IL-13Ra2) overexpression in LSL-KrasG12D/+, LSL-Try53R172H/+, and PDx-1-Cre (KPC) genetically engineered mouse model of pancreatic ductal adenocarcinoma as a target for receptor directed anticancer therapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a uniformly lethal disease because it escapes early diagnosis and at an advanced stage there are no effective therapies available. Previously, we have demonstrated that IL-13R α2 is overexpressed in 71% of human PDA specimens. We have targeted IL-13Rα2 in an orthotopic mouse model of human PDA and shown effectiveness of the receptor targeting agent, IL-13-PE, a recombinant immunotoxin comprised of IL-13 and Pseudomonas exotoxin. To determine the effectiveness of IL-13-PE and develop receptor targeting approaches, we used a LSL-KrasG12D/+, LSL-Try53R172H/+ and PDx-1-Cre (KPC) genetically engineered mouse model that spontaneously develops PDA in C57BL/6J immunocompetent mice and simulates human PDA disease. These spontaneous PDA tumors showed significant overexpression of IL-13R α2 mRNA compared to normal mouse pancreas and surrounding non-cancerous pancreatic tissues as determined by RT-qPCR. By in situ hybridization (ISH) and immunohistochemistry (IHC) analysis, we confirmed these results at mRNA and protein levels of tumor and non-tumor tissue specimens by hybridizing the tumor sections with biotinylated anti-sense riboprobe and immunostaining with anti-murine IL-13R α2 antibody. We established two tumor cell lines from KPC mice PDA, which maintained abundant expression of IL-13R α2 mRNA and protein levels. The overexpressed IL-13R α2 on PDA tumor cells is found biologically active, as it binds to IL-13-PE in a concentration dependent manner killing tumors cells at IC50 of ~25ng/ml (concentration of IL-13-PE that killed 50% of tumor cells). In a clonogenic assay, PDA tumor cells formed colonies, which were again sensitive to IL-13-PE in a concentration dependent manner with IC50 of ~28ng/ml. Based on these data, we have initiated assessment of anti-cancer activity of IL-13-PE against spontaneously developed PDA tumors developed in mice between the ages of 14-16 weeks. These mice were randomized to either receive excipient control i.p. or 50 µg/Kg IL-13-PE every alternate day for two weeks and then evaluated for general health and tumor growth by ultrasound technique. Five week follow up data reveal that mice treated with excipient alone developed larger tumors compared to treated mice and the general health of IL-13-PE treated mice was better compared to excipient-treated mice. These animals are being followed for their overall survival. Our studies indicate that IL-13R α2 is overexpressed in genetically engineered mouse model of PDA suggesting that IL-13R α 2 is a useful drug target not only in orthotopic mouse model but also in spontaneously developed PDA in mice, which may mimic its biological function more closely to human PDA. Citation Format: Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri. Identification of interleukin 13 receptor alpha 2 (IL-13Ra2) overexpression in LSL-KrasG12D/+, LSL-Try53R172H/+, and PDx-1-Cre (KPC) genetically engineered mouse model of pancreatic ductal adenocarcinoma as a target for receptor directed anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1928.