Translating N-Cadherin Targeted Therapy in Castrate Resistant Prostate Cancer

去势抵抗性转移性疾病是晚期前列腺癌男性发病和死亡的主要原因。转移和去势抵抗的分子机制是多种多样的，只有部分定义。迫切需要针对这些靶点的新靶点和疗法来对抗晚期前列腺癌。同样，针对多个关键靶点的合理联合治疗也是迫切需要的。我们最近发现并“认可”N-钙粘蛋白作为一种新的靶点， 有助于前列腺癌的转移和去势抵抗，并且是前列腺癌的转移和去势抵抗所必需的。我们有 在临床前研究中开发并验证了靶向N-钙粘蛋白的鼠单克隆抗体。这 抗体能够阻断转移，抑制生长，并延迟多个前列腺的去势抵抗 体内的癌细胞系和异种移植物。初步研究揭示了 N-钙粘蛋白和N-钙粘蛋白靶向抗体可能起作用的途径。这些数据支持小说 假设N-钙粘蛋白是去势抵抗性前列腺癌（CRPC）重要分子驱动因子 和治疗晚期前列腺癌的新靶点。这项拨款提案的总体目标是 将N-cadherin靶向抗体疗法应用于临床。为此，我们将首先研究 N-cadherin对雄激素受体（AR）的表达，并确定N-cadherin是否能够介导 对AR靶向治疗的耐药性。接下来，我们将评估合理的治疗组合， 增强或协同结合N-钙粘蛋白的抗体。这些组合将基于 检查N-钙粘蛋白信号传导。第三，我们将产生一种能够进入 在临床前模型中评价其毒性、药代动力学和治疗活性。年底 在这个项目中，我们应该知道用N-钙粘蛋白抗体治疗谁，如何优化这种抗体的靶向， 途径，并有一个领先的生物，可以制造和带到临床。

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.