Translating N-Cadherin Targeted Therapy in Castrate Resistant Prostate Cancer

N-钙粘蛋白靶向治疗在去势抵抗性前列腺癌中的应用

基本信息

批准号：
8760358
负责人：
ROBERT E REITER
金额：
$ 25.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8760358
关键词：
Affect Affinity Androgen Antagonists Androgen Receptor Animal Model Antibodies Antibody Therapy Applications Grants Binding Biological Cancer Etiology Castration Cessation of life Clinic Clinical Combined Modality Therapy Complement Data Development Disease Disease Resistance Drug Kinetics Epitopes Goals Growth Human Image Lead Malignant neoplasm of prostate Mediating Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus N-Cadherin NF-kappa B Neoplasm Metastasis PC3 cell line Pathway interactions Patients Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Positioning Attribute Pre-Clinical Model Preparation Proto-Oncogene Proteins c-akt Resistance Role Signal Transduction Signal Transduction Pathway Testing Therapeutic Therapeutic antibodies Toxic effect Translating Xenograft procedure animal tissue base cancer therapy candidate selection castration resistant prostate cancer combat improved in vitro Assay in vivo men mortality next generation novel novel therapeutics preclinical study response tumor

项目摘要

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.

耐cast割的转移性疾病是晚期前列腺癌男性发病率和死亡率的主要原因。基础转移和cast割耐药性的分子机制既多样化，也仅部分定义。迫切需要针对这些靶标的针对这些靶标的新型靶标和疗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理性组合疗法。我们最近确定并“证明” N-钙黏着蛋白是一个新颖的目标对前列腺癌的转移和cast割耐药性有助于并需要。我们有在临床前研究中开发和验证了一种靶向N-钙粘着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cast割耐药性癌细胞系和异种移植体体内。初步研究发现了信号转导 N-钙粘着蛋白和靶向N-钙粘着蛋白的抗体可以起作用的途径。这些数据支持小说假设N-钙粘着蛋白是castration抗性前列腺癌（CRPC）的重要分子驱动力以及治疗晚期前列腺癌的新目标。该赠款提案的总体目标是将靶向N-钙粘蛋白的抗体疗法转化为诊所。为此，我们将首先研究 N-钙粘蛋白表达对雄激素受体（AR），并确定N-钙粘蛋白是否能够介导对AR靶向疗法的抗性。接下来，我们将评估可能的理性治疗组合增强或与结合N-钙粘蛋白的抗体协同作用。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的人类（Ized）抗体该诊所并评估其临床前模型中其毒性，药代动力学和治疗活性。在最后在这个项目中，我们应该知道用N-钙粘蛋白抗体治疗谁，如何优化目标途径，并具有可以制造并带入诊所的铅生物学。