Abstract 3932: IL13Rα2 regulates cell invasion, and is a therapeutic target for adrenocortical carcinoma

Abstract

Abstract Adrencortical neoplasms are one of the most common human neopolasms. Furthermore, it is difficult to distinguish localized benign from malignant adrenal tumors. Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options for patients with advanced and metastatic disease. Several genome wide expression studies have shown overexpression of Interleukin-13 Receptor alpha2 (IL13Rα2) in some human malignancies but the function of this gene in cancer cells is poorly understood. We evaluated IL13Rα2 mRNA expression in normal (n=21), and in benign (n=78) and malignant (n=10) adrenocortical tumors. We found 11-fold higher expression in malignant tumors compared to benign (p<0.05) and absent expression in normal adrenocortical tissue. Immunohistochemistry analysis confirmed high protein expression in malignant and benign tumors and absent expression in normal adrenocortical tissues (p<0.05). IL13Rα2 mRNA expression level also had 90% accuracy for distinguishing benign from malignant adrenocortical tumors. We used IL13Rα2 siRNA knockdown to assess its effect on cell proliferation and cell invasion in the NCI H295R cell line, which expressed high levels of IL13Rα2. IL13Rα2 knockdown did not significantly affect cell proliferation but did decrease invasion by 60% as compared to negative control (p<0.05). To determine the significance of IL13Rα2 as a therapeutic target for ACC, we evaluated the sensitivity in two ACC cell lines (NCI-H295R with high IL13Rα2 expression and SW13 with low IL13Rα2 expression) to a highly specific IL-13 targeting immunotoxin (IL-13-PE). We found the IC50 for IL-13-PE was 1.3ng/ml (NCI-H295R) and 1000ng/ml (SW13) in the cell lines. Based on this observation, we then tested the efficacy of IL-13-PE therapy in an ACC xenograft model in athymic nude mice. Mice receiving either intratumoral or intraperitoneal IL-13-PE therapy as compared to control showed a significant reduction in tumor size as well as tumor necrosis (p<0.05), and had prolonged survival (p<0.05). Both routes of IL-13-PE administration were well tolerated with no significant toxicity. Our study indicates that IL13Rα2 is overexpressed in 100% of ACC, is a good diagnostic marker for ACC, regulates ACC cell invasion, and is a novel therapeutic target for the treatment of ACC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3932. doi:1538-7445.AM2012-3932