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是一个从UAB孢子的职业发展计划开发的新项目 在乳腺癌中。 PI最初开发了一种新型的抗DR5单克隆抗体Tra-8，该抗体表现出 没有肝细胞细胞毒性的对癌细胞的强大凋亡活性。在支持 职业发展基金并与我们的工业赞助商Sankyo Co，Ltd，Tra-8合作 在临床前研究中探讨了，并已成为抗癌候选人的发展。这 该提案的竞争更新的总体目标是制定有效的治疗策略 通过与新型的单克隆Tra-8结合选择性靶向DR5来治疗乳腺癌 化学疗法。中心假设是乳腺癌和其他癌细胞可能会差异表达 在恶性转化过程中提高DR5的水平，并且可以通过 激动性单克隆抗体直接诱导癌细胞凋亡。作为Tra-8和化学疗法 代理商可能利用不同但互补的途径来触发凋亡，乳房的敏感性 化学疗法剂可以增强癌细胞至Tra-8介导的凋亡。此外，Tra-8 可以通过预防或逆转乳腺癌的化学抗性来提高化学疗法的疗效 细胞。有四个具体的目的：目标1是检查带有和没有的tra-8（anti-dr5）的功效 鼠类原位和转移性人类乳腺癌的鼠模型中的化学疗法剂；目标2是 表征DR5/DDX3途径在调节乳腺癌细胞敏感性或耐药性中的作用 Tra-8诱导凋亡的线，并表征人类乳腺癌中的DR5/DDX3途径 组织样品；目标3是确定组合疗法的体外和体内协同机制 使用Tra-8和化学疗法； AIM 4是启动CS-1008（人源化Tra-8）的临床开发 乳腺癌。拟议的基本和翻译研究将支持拟议的临床研究。 这些研究的完成将为乳腺癌提供新的且潜在的有效疗法。 这项研究的目的是评估一种用于治疗乳腺癌的新抗体。研究 将确定最大化抗体与化学疗法的功效的机制 以及用于预测临床试验中患者反应的生物标志物的发展。