Castration resistant metastatic disease is the major cause of morbidity and mortality in men with advanced prostate cancer. The molecular mechanisms underlying metastasis and castration resistance are both varied and only partially defined. Novel targets and therapies directed against these targets are urgently needed to combat advanced prostate cancer. Likewise, rational combination therapies directed against multiple critical targets are urgently needed. We have recently identified and credentialed N-cadherin as a novel target that contributes to and is required for both metastasis and castration resistance in prostate cancer. We have developed and validated in preclinical studies a murine monoclonal antibody that targets N-cadherin. This antibody is able to block metastasis, inhibit growth, and delay castration resistance of multiple prostate cancer cell lines and xenografts in vivo. Preliminary studies have uncovered the signal transduction pathways by which N-cadherin and N-cadherin-targeted antibody may act. These data support the novel hypothesis that N-cadherin is a significant molecular driver of castration resistant prostate cancer (CRPC) and a novel target for treatment of advanced prostate cancer. The overall goal of this grant proposal is to translate N-cadherin-targeted antibody therapy to the clinic. To do so, we will first examine the relationship of N-cadherin expression to the androgen receptor (AR) and determine whether N-cadherin is able to mediate resistance to AR-targeted therapies. Next, we will evaluate rational treatment combinations that might augment or synergize with antibodies that bind N-cadherin. These combinations will be based on an examination of N-cadherin signaling. Third, we will generate a lead human(ized) antibody capable of entering the clinic and evaluate its toxicity, pharmacokinetics and therapeutic activity in preclinical models. At the end of this project, we should know who to treat with N-cadherin antibodies, how to optimize targeting of this pathway, and have a lead biologic that can be manufactured and taken forward into the clinic.