Abstract 677: Co-targeting of AR and N-cadherin with Enzalutamide and 2A9 monoclonal antibody to treat castration resistant prostate cancer

Abstract

Abstract Introduction: Enzalutamide (MDV3100) is an androgen receptor (AR) antagonist that targets various stages of the AR signaling pathway, and has been approved for the treatment of castration resistant prostate cancer (CRPC). Studies show improved survival in men with metastatic CRPC after chemotherapy when treated with Enzalutamide. However, emergence of potential AR-independent mechanisms of castration resistance and resistance to these next generation AR inhibitors has proven to be a challenge. Previously, we reported an association of N-cadherin, a mesenchymal cadherin expressed on the cell surface, with tumor progression and castration resistance. Targeting N-cadherin positive cells with specific monoclonal antibodies affect tumor growth in both AR positive and negative prostate cancers. Here we investigate the effects of co-targeting AR with Enzalutamide and N-cadherin with the N-cadherin specific monoclonal antibody 2A9 in CRPC. Method: N-cadherin was ectopically expressed in androgen dependent prostate cancer cells (LNCaP, MDA-PCa-2b, VCaP) and evaluated in vitro for invasion, growth, and self-renewal in the presence of Enzalutamide and 2A9 monoclonal antibody, raised against extracellular domain 4 of N-cadherin. Enzalutamide-resistant cell lines were generated and characterized. For in vivo studies, castration resistant N-cadherin and AR positive, as well as androgen-dependent tumors were implanted in mice as xenografts. When the tumors reached 100mm^3 in volume, mice were castrated and treated with 5-10mg/kg Enzalutamide and/or 5-10mg/kg 2A9 and monitored for tumor growth, local invasion, and metastasis. The tumors were harvested and analyzed for cell proliferation, apoptosis, and other markers. Results: Ectopic expression of N-cadherin in N-cadherin negative cells showed increase in cell growth and invasion in androgen-deprived conditions. In vitro studies show single or combination treatment of N-cadherin positive and AR positive cells reduce invasion and cell proliferation. Enzalutamide-resistant cell lines show response to 2A9 in androgen-deprived conditions. In vivo studies using CRPC xenograft models expressing N-cadherin and AR show inhibition of tumor growth when the animals are castrated and treated with a combination of Enzalutamide and 2A9 than either treatment alone. Androgen dependent xenograft models in castrated mice also showed significant delay in progression to castration resistance when treated in combination than either treatment alone. Conclusion: Previous studies suggested that therapeutic targeting of N-cadherin with monoclonal antibodies have significant effect in inhibiting tumor progression. The antibody in combination with Enzalutamide showed synergy. Other androgen receptor antagonists and other drugs targeting those potentially involved in downstream pathways may prove to have additional clinical benefit. Citation Format: Evelyn A. Kono, Sean Hyung-Kwon Lee, Tatsuya Shimomura, Shu Lin, Joyce Yamashiro, Robert E. Reiter. Co-targeting of AR and N-cadherin with Enzalutamide and 2A9 monoclonal antibody to treat castration resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 677. doi:10.1158/1538-7445.AM2014-677