Translating N-Cadherin Targeted Therapy in Castrate Resistant Prostate Cancer

抗去势转移疾病是晚期前列腺癌患者发病率和死亡率的主要原因。转移和去势抵抗的分子机制都是不同的，并且只有部分确定。迫切需要针对这些靶点的新靶点和治疗方法来对抗晚期前列腺癌。同样，迫切需要针对多个关键目标的合理组合疗法。我们最近已经确定N-钙粘附素是一个新的靶点，并将其命名为 有助于前列腺癌的转移和抵抗去势，并且是前列腺癌所必需的。我们有 开发并在临床前研究中验证了一种针对N-钙粘附素的鼠源性单抗。这 抗体能阻断多发性前列腺的转移，抑制生长，延缓去势抵抗 体内癌细胞系和异种移植瘤。初步研究已经发现了信号转导 N-钙粘素和N-钙粘素靶向抗体的作用途径。这些数据支持这部小说 N-钙粘附素是抗去势前列腺癌(CRPC)的重要分子驱动因素的假说 以及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-钙粘素靶向抗体疗法推向临床。要做到这一点，我们首先要考察 N-钙粘附素与雄激素受体(AR)的表达并确定N-钙粘附素是否能够介导 对AR靶向治疗的抵抗。接下来，我们将评估合理的治疗组合， 增强或协同结合N-钙粘素的抗体。这些组合将基于 N-钙粘素信号转导的检测。第三，我们将产生一种能够进入人体的先导抗体。 并在临床前模型中评估其毒性、药代动力学和治疗活性。在最后 对于这个项目，我们应该知道用N-钙粘素抗体治疗谁，如何优化靶向 途径，并有一种铅生物，可以制造和推进到临床。

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.