Abstract 1581: IL-13 mediates signal transduction through IL-13 receptor α2 in pancreatic ductal adenocarcinoma: role of IL-13 pseudomonas exotoxin in pancreatic cancer therapy

Abstract

Abstract Purpose: Interleukin-13 receptor alpha 2 (IL-13Rα2) is a tumor antigen, which is overexpressed in certain human tumors. However, its expression and significance in pancreatic cancer and whether IL-13 can signal through IL-13Rα2 in cancer is not known. In addition, it is not known whether IL-13-PE can target pancreatic cancer for therapy. Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by IHC; and in cell lines by flow cytometry and RT-PCR. The role of IL-13Rα2 was examined by IL-13 induced signaling in pancreatic cancer cell lines. IL-13Rα2 positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in orthotopic murine model of human pancreatic cancer. Results: Seventy one percent pancreatic tumor samples overexpressed moderate- to high-density IL-13Rα2 compared to normal pancreatic samples. IL-13 induced TGF-β1 promoter activity in IL-13Rα2 positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2-negative or RNAi knockdown cells. c-Jun and c-Fos of AP-1 family nuclear factors were activated by IL-13 only in IL-13Rα2-positive cells. In orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole body imaging. In addition, IL13-PE prolonged the mean survival time of treated animals. Similar results were observed in mice xenografted orthotopically with a surgically resected human pancreatic tumor sample. Conclusions: These results indicate that IL-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes TGF-β activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1581.