DR5 Antibody Therapy for Breast Cancer

项目2是一个新的项目，从UAB SPORE的职业发展计划发展而来。 在乳腺癌中。PI最初开发了一种新型抗DR 5单克隆抗体TRA-8，其表现出 对癌细胞具有强的细胞毒性诱导活性，而无肝细胞毒性。的支持下 职业发展基金，并与我们的工业赞助商，三共有限公司，TRA-8合作， 已在临床前研究中探索，并已作为抗癌候选药物进入开发阶段。的 本竞争性更新提案的总体目标是制定有效的治疗策略， 通过用新的单克隆TRA-8选择性靶向DR 5与 化疗核心假设是乳腺癌和其他癌细胞可能在乳腺癌细胞中 在恶性转化过程中增加DR 5的水平，并且DR 5可以选择性地用 激动性单克隆抗体直接诱导癌细胞凋亡。作为TRA-8和化疗 药物可以利用不同但互补的途径来触发细胞凋亡，乳腺癌的易感性， 癌细胞对TRA-8介导的细胞凋亡的耐受性可通过化疗剂增强。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 细胞有四个具体目的：目的1是检查TRA-8（抗DR 5）在有和没有 在原位和转移性人乳腺癌的鼠模型中使用化疗剂;目的2是 表征DR 5/DDX 3通路在调节乳腺癌细胞的敏感性或抗性中的作用 细胞系中的细胞凋亡，并表征人乳腺癌中的DR 5/DDX 3途径 目的3是确定联合治疗的体外和体内协同机制 与TRA-8和化疗联合使用;目标4是启动CS-1008（人源化TRA-8）的临床开发， 乳腺癌拟定的基础和转化研究将支持拟定的临床研究。 这些研究的完成将为乳腺癌提供一种新的和潜在的有效治疗方法。 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 将确定抗体与化疗联合使用的最大功效的机制， 以及开发用于预测临床试验中患者反应的生物标志物。

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.