Abstract 867: IGF-I receptor targeting therapy for esophageal carcinomas.

Abstract

Abstract Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and cancer development of many malignancies, however this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of worst prognostic disease, main types of which are squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously we have reported that the IGF axis may play a key role in tumor progression of ESCC and its detection may be useful for the prediction of recurrence and poor prognosis and possibly for selecting patients for targeting therapy for IGF-IR. We have previously shown successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative forms of IGF-IR (Ad-IGF-IR/dn). In this study, we wanted to develop potential targeted therapeutics to IGF-1R; therefore, we assessed the effect of IGF-IR blockade in both types of esophageal cancer. We analyzed immunohistochemical expression of IGF-IR in a tissue array. A tyrosine kinase inhibitor, BMS-536924, and Ad-IGF-IR/dn were used to treat several ESCC lines, such as TE1, TE8, TT, TTn, and EAC lines, including OE19 and OE33. We assessed the effect of both IGF-IR blockade on signal transduction, growth, and apoptosis. IGF-IR is expressed frequently in esophageal tumors, but not in normal mucosa. IGF-IR was produced in ESCC more than EAC, and is detected in metastasized similar to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both types of cancer. Blockade of IGF-IR up-regulated both stress- and chemotherapy-induced apoptosis in both esophageal tumor type. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. Thus, the IGF axis may play a key role in tumor progression of human esophageal carcinomas. The IGF-IR targeting strategies might be useful anticancer therapeutics which can be used widely for human esophageal malignancies. Citation Format: Yasushi Adachi, Hiroyuki Yamamoto, Hirokazu Ohashi, Yasutaka Matsunaga, Katsuhiko Nosho, Hiromu Suzuki, Hiroaki Taniguchi, Yoshiaki Arimura, Takao Endo, Yasuo Kato, Kohzoh Imai, David P. Carbone, Yasushisa Shinomura. IGF-I receptor targeting therapy for esophageal carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 867. doi:10.1158/1538-7445.AM2013-867