Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer

卵巢癌死亡受体介导的细胞凋亡和治疗策略

基本信息

批准号：
7264774
负责人：
TONG ZHOU
金额：
$ 33.92万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-20 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7264774
关键词：
Address Adriamycin PFS Affect Apoptosis Apoptotic Applications Grants Biological Assay Biological Markers Boxing Cancer Patient Cancer cell line Carboplatin Cell Death Cell surface Cessation of life Clinical Clinical Trials Collaborations Combination Chemotherapy Combined Modality Therapy Complex Data Death Domain Development Engineering Exhibits Funding Future Goals Hepatocyte Human In Vitro Industry K-Series Research Career Programs Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Molecular Profiling Molecular Target Monoclonal Antibodies Mus Normal Cell Ovarian Carcinoma Paclitaxel Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase Play Predisposition Protein Family Proteins Proteomics Protocols documentation RNA Helicase Regulation Reproduction spores Research Personnel Resistance Role Sampling Signal Transduction Slice Staging TNF-related apoptosis-inducing ligand TNFRSF10A gene TNFRSF10B gene Techniques Technology Therapeutic Tissue Slice Technology Tissues Toxic effect Treatment Efficacy Tumor Cell Line Work Xenograft Model cancer cell chemotherapeutic agent chemotherapy clinical efficacy cytotoxicity genetic regulatory protein in vivo neoplastic cell novel ovarian neoplasm preclinical study programs receptor response tumor

项目摘要

DESCRIPTION (provided by applicant): Our investigative team has developed a novel anti-DR5 monoclonal antibody (TRA-8) which triggers apoptosis and cytotoxicity to a variety of tumor cell lines including ovarian cancer. The TRA-8 mediated cytotoxicity and in vivo anti-tumor efficacy in murine xenograft models is markedly enhanced in combination with chemotherapy drugs (Adriamycin, Taxol, Carboplatin, Camptostar, etc.). In collaboration with our industry partner (Sankyo Co., Ltd.), a humanized construct of TRA-8 has been generated (CS-1008). The central hypothesis of this proposal is that ovarian cancer tumor cells from patients express elevated levels of DR5 expression and enhanced anti-DR5 mediated apoptosis resulting in TRA-8 mediated anti-tumor efficacy as a single agent or in combination with chemotherapy. The key apoptosis regulatory proteins around the death domain of DR5 determine the susceptibility of tumor cells to TRA-8 mediated apoptosis which may be used as a biomarker for selection of patients likely to benefit from huTRA-8 therapy. These apoptosis regulatory proteins may serve as targets of chemotherapy for further enhancement of TRA-8 efficacy. There are four Specific Aims: Aim 1: To determine TRA-8-induced cytotoxicity and its correlation with expression of apoptosis-associated proteins in primary ovarian carcinoma tissues. Aim 2: To determine the correlation of the DR5/DDX3-associated clAP1 with the susceptibility to TRA-8-mediated apoptosis of ovarian cancer cell lines and patient ovarian cancer tissues as a putative biomarker for predicting tumor cell response to TRA-8. Aim 3: To determine how modulation of DDX3 affects TRA-8 mediated apoptosis and how chemotherapeutic agents which enhance TRA-8-mediated apoptosis affect the DR5/DDX3 protein complex in human ovarian cancer cell lines both in vitro and in vivo. Aim 4: To carry out a phase I/II protocol of huTRA-8 (CS-1008) plus combination chemotherapy in Stage Illc and IV ovarian cancer patients. This trial will correlate TRA-8 and drug cytotoxicity assays (tissue slice technique), apoptotic protein profile and DR5/DDX3 complex analysis with clinical efficacy as well as provide a reasonable estimate of therapeutic efficacy.

描述（由申请人提供）：我们的调查团队开发了一种新型的抗DR5单克隆抗体（TRA-8），该抗体将凋亡和细胞毒性触发到包括卵巢癌在内的多种肿瘤细胞系。在鼠异种移植模型中，Tra-8介导的细胞毒性和体内抗肿瘤疗效与化学疗法药物（Adriamcin，cansol，紫杉醇，卡氏蛋白酶，Camptostar等）相结合显着增强。与我们的行业合作伙伴（Sankyo Co.，Ltd.）合作，已经生成了TRA-8的人源化结构（CS-1008）。该提议的中心假设是，来自患者的卵巢癌肿瘤细胞表达了DR5表达水平升高，抗DR5介导的凋亡增强，导致Tra-8介导的抗肿瘤疗效作为单一药物或与化学疗法结合使用。 DR5死亡结构域周围的关键凋亡调节蛋白决定了肿瘤细胞对TRA-8介导的凋亡的敏感性，该蛋白质可用作可从Hutra-8治疗中受益的患者的生物标志物。这些细胞凋亡调节蛋白可以作为化学疗法的靶标，以进一步增强TRA-8疗效。有四个特定的目的：目标1：确定Tra-8诱导的细胞毒性及其与原发性卵巢癌组织中与凋亡相关蛋白的表达的相关性。目的2：确定DR5/DDX3相关的CLAP1与Tra-8介导的卵巢癌细胞系和患者卵巢癌组织的凋亡的易感性，作为预测肿瘤细胞对TRA-8的反应的推定生物标志物。目标3：确定DDX3的调节如何影响Tra-8介导的凋亡以及如何增强Tra-8介导的凋亡的化学治疗剂如何影响人类卵巢癌细胞系的DR5/DDX3蛋白质复合物，包括体外和体内。 AIM 4：在ILLC和IV卵巢癌患者中执行HUTRA-8（CS-1008）的I/II期方案。该试验将将Tra-8和药物细胞毒性测定（组织切片技术），凋亡蛋白谱和DR5/DDX3复合物分析与临床功效相关联，并提供对治疗功效的合理估计。