DR5 Antibody Therapy for Breast Cancer

乳腺癌 DR5 抗体治疗

• 批准号: 7290715
• 负责人: TONG ZHOU
• 金额: $ 32.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290715
• 关键词: Address; Adjuvant; Adverse effects; Aftercare; Antibodies; Antibody Therapy; Apoptosis; Appendix; Applications Grants; Biological Markers; Boxing; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Center; Cancer cell line; Caspase; Cell Death; Cell Line; Cell surface; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Collaborations; Combination Chemotherapy; Combined Modality Therapy; Complex; Death Domain; Development; Disseminated Malignant Neoplasm; Dose; Drug Administration Schedule; Drug Delivery Systems; Drug Kinetics; Drug usage; Engineering; Evaluation; Exhibits; Funding; Future; Goals; Guanosine Monophosphate; Hepatocyte; Heterogeneity; Human; Implant; In Vitro; Induction of Apoptosis; Investigation; K-Series Research Career Programs; Licensing; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mentors; Modeling; Molecular Profiling; Molecular Target; Monoclonal Antibodies; Mus; Normal Cell; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Population; Predisposition; Primates; Production; Program Development; Property; Protein Family; Proteins; Proteomics; Quality Control; RNA Helicase; Recruitment Activity; Regulation; Reproduction spores; Research; Research Personnel; Resistance; Rest; Role; Schedule; Signal Transduction; TNF-related apoptosis-inducing ligand; TNFRSF10A gene; TNFRSF10B gene; Tail; Technology; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Tissues; Toxic effect; Toxicology; Translating; Treatment Efficacy; Treatment Protocols; United States Food and Drug Administration; Work; Xenograft Model; assay development; cancer cell; cancer therapy; career; chemotherapeutic agent; chemotherapy; clinical efficacy; clinically relevant; cytotoxicity; drug development; genetic regulatory protein; improved; in vivo; malignant breast neoplasm; neoplastic cell; nonhuman primate; novel; pre-clinical; preclinical study; prevent; programs; receptor; response; subcutaneous; therapeutic target; translational study; trend; tumor; tumor growth

Project 2 is a new project that has developed from the Career Development Program of the UAB SPORE in Breast Cancer. The PI initially developed a novel anti-DR5 monoclonal antibody, TRA-8, which exhibited a strong apoptosis-inducing activity against cancer cells without hepatocyte cytotoxicity. With the support of the Career Development funds and in collaboration with our industrial sponsor, Sankyo Co, Ltd, TRA-8 has been explored in pre-clinical studies and has moved into development as an anti-cancer candidate. The overall goal of this proposal for the competitive renewal is to develop an effective therapeutic strategy for treatment of breast cancer by selectively targeting DR5 with a novel monoclonal TRA-8 in combination with chemotherapy. The central hypothesis is that breast and other cancer cells may differentially express increasing levels of DR5 during malignant transformation and that DR5 can be selectively targeted with an agonistic monoclonal antibody to directly induce apoptosis of cancer cells. As TRA-8 and chemotherapy agents may utilize different but complementary pathways to trigger apoptosis, the susceptibility of breast cancer cells to TRA-8-mediated apoptosis can be enhanced by chemotherapy agents. Furthermore, TRA-8 may improve the efficacy of chemotherapy by preventing or reversing chemo-resistance in breast cancer cells. There are four Specific Aims: Aim 1 is to examine the efficacy of TRA-8 (anti-DR5) with and without chemotherapy agents in murine models of orthotopic and metastatic human breast cancer; Aim 2 is to characterize the role of the DR5/DDX3 pathway in modulating sensitivity or resistance of breast cancer cell lines to TRA-8 induction of apoptosis, and to characterize the DR5/DDX3 pathway in human breast cancer tissue samples; Aim 3 is to determine in vitro and in vivo synergistic mechanisms of combination therapy with TRA-8 and chemotherapy; Aim 4 is to initiate clinical development of CS-1008 (humanized TRA-8) in breast cancer. The proposed basic and translational studies will support the proposed clinical studies. Accomplishment of these studies will yield a new and potentially effective therapy for breast cancer. The goal of this research is to evaluate a new antibody for the treatment of breast cancer. The research will identify the mechanisms for maximizing the efficacy of the antibody in combination with chemotherapy and the development of biomarkers for predicting the response of patients in clinical trials.

项目2是从UAB SPORE职业发展计划发展而来的新项目 在乳腺癌中。 PI最初开发了一种新型抗DR5单克隆抗体TRA-8，该抗体表现出 对癌细胞有很强的细胞凋亡诱导活性，但没有肝细胞毒性。在以下人士的支持下 职业发展基金并与我们的工业赞助商 Sankyo Co, Ltd 合作，TRA-8 已 在临床前研究中进行了探索，并已作为抗癌候选药物进入开发阶段。这 该竞争性更新提案的总体目标是制定有效的治疗策略 通过使用新型单克隆 TRA-8 选择性靶向 DR5 并结合 化疗。中心假设是乳腺癌和其他癌细胞可能差异表达 恶性转化过程中 DR5 水平增加，并且 DR5 可以选择性地靶向 激动性单克隆抗体可直接诱导癌细胞凋亡。作为 TRA-8 和化疗 药物可能利用不同但互补的途径来触发细胞凋亡、乳腺癌的易感性 化疗药物可以增强TRA-8介导的癌细胞凋亡。此外，TRA-8 可以通过预防或逆转乳腺癌的化疗耐药性来提高化疗的疗效 细胞。有四个具体目标： 目标 1 是检查 TRA-8（抗 DR5）在使用和不使用的情况下的功效 原位和转移性人类乳腺癌小鼠模型中的化疗药物；目标 2 是 表征 DR5/DDX3 通路在调节乳腺癌细胞敏感性或耐药性中的作用 TRA-8 诱导细胞凋亡，并表征人类乳腺癌中的 DR5/DDX3 通路 组织样本；目标 3 是确定联合治疗的体外和体内协同机制 TRA-8 和化疗；目标 4 是启动 CS-1008（人源化 TRA-8）的临床开发 乳腺癌。拟议的基础和转化研究将支持拟议的临床研究。 这些研究的完成将产生一种新的、可能有效的乳腺癌治疗方法。 这项研究的目的是评估一种治疗乳腺癌的新抗体。研究 将确定抗体与化疗联合发挥最大功效的机制 以及开发用于预测临床试验中患者反应的生物标志物。