Abstract 632: The efficacy of IGF-I receptor monoclonal antibody for human gastrointestinal carcinomas is independent for mutation status of k-ras

Abstract

Abstract Background & Aims: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of many tumors, including gastrointestinal cancers. We have previously shown successful therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in the patients with gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation. Methods: We assessed the effect of figitumumab on signal transduction, proliferation, and survival in 6 gastrointestinal cancer cell lines with or without k-ras mutation, colon and pancreatic adenocarcinoma, esophageal squamous cancer; and hepatoceller carcinoma. Combination effects of figitumumab and chemotherapy were studied. Then figitumumab was evaluated in the treatment for human gastrointestinal. cancer xenografts in nude mice. Results: Figitumumab blocked autophosphorylation of IGF-IR and the downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. The drug inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis in all cell lines. Moreover, the combination of the monoclonal antibody and chemotherapy was effective against tumors on mice. The effect of figitumumab is not influenced by the mutation stasis of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in tumors on mice. The drug did not affect on neither murine body weight nor blood concentrations of glucose, insulin, IGFBP-3, and growth hormone. Conclusions: IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic utility in human gastrointestinal carcinomas even if k-ras mutated types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 632. doi:10.1158/1538-7445.AM2011-632