Abstract 5052: N-cadherin monoclonal antibody as a therapeutic agent against chemoresistance in prostate cancer

Abstract

Abstract Introduction: The development of chemoresistance is a formidable obstacle in realizing effective therapy against cancer. Docetaxel is a common therapeutic agent given to men with castration-resistant prostate cancer (CRPC). However, a number of patients show poor response or eventually develop resistance to the treatment. N-cadherin, a calcium-dependent cell-cell adhesion surface protein associated with Epithelial to mesenchymal transition (EMT), is implicated in castration resistance and metastasis in prostate cancer. We have shown in previous studies that monoclonal antibodies raised against the extracellular domain of N-cadherin have potential therapeutic effects in castration-resistant tumor growth and metastasis. In this study, our objective is to determine the role of N-cadherin expression in chemoresistance and whether treatment with monoclonal antibodies restores chemosensitivity. Methods: N-cadherin was ectopically expressed in N-cadherin negative prostate cancer cells (LNCaP, MDA PCa 2b). For in vitro experiments, these models were used to evaluate cytotoxicity and apoptosis in the presence of docetaxel. Endogenously expressing N-cadherin were either treated with monoclonal antibodies raised against the extracellular domain of N-cadherin or N-cadherin expression was reduced by siRNA knockdown. For in vivo studies, monoclonal antibodies raised against N-cadherin were used in combination with docetaxel to treat N-cadherin positive xenografts, and tumor growth monitored over time. Results: Ectopic expression of N-cadherin in N-cadherin negative cells resulted in >25-fold increase in resistance to cytotoxicity by docetaxel treatment when compared with control cells. N-cadherin knockdown by siRNA of cells endogenously expressing N-cadherin resulted in an increase of cytotoxicity in response to docetaxel when compared with cells transfected with scramble siRNA. Treatment with monoclonal antibody also resulted in increase of cytotoxicity in response to docetaxel. In vitro studies also show that increase in N-cadherin leads to upregulation in NFkB (>2.5-fold ± 0.17 increase in activity) and Toll-like receptor signaling, which are implicated in chemoresistance. Preliminary in vivo studies show some additive effect monoclonal antibodies against N-cadherin in combination with docetaxel on growth of xenograft tumors expressing N-cadherin. Conclusions: These studies suggest that N-cadherin is involved in the development of chemoresistance in prostate cancers. Therapeutic targeting of N-cadherin with monoclonal antibodies, in combination with therapeutic agents such as docetaxel may have significant clinical benefit. Future experiments involve further elucidating the pathways involved and downstream targets, such as those involved in NFkB and Toll-like receptor signaling. 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 5052. doi:10.1158/1538-7445.AM2011-5052