Targeted Intervention Against EphA2 on Cancer Cells

EphA2对癌细胞的靶向干预

• 批准号: 6522671
• 负责人: DEBORAH W KNAPP
• 金额: $ 22.62万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522671
• 关键词: athymic mouse; breast neoplasms; cooperative study; enzyme activity; metastasis; monoclonal antibody; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer invasiveness; neutralizing antibody; nonhuman therapy evaluation; prostate neoplasms; protein kinase

DESCRIPTION: (Provided by Applicant) Elevated levels of tyrosine kinase activity are necessary the growth and dissemination of malignant carcinoma cells. Our laboratory recently applied new technologies in monoclonal antibody production and identified dramatic changes in the expression and function of the EphA2 tyrosine kinase in malignant carcinomas. EphA2 is overexpressed in cancer cells (by 50-500 fold), with the highest levels of EphA2 consistently found on cells with metastatic potential. We have also shown that EphA2 overexpression confers metastatic potential but that the growth and invasiveness of metastatic cells can be reversed by activating EphA2 at the cell surface. Based on these results, we hypothesize that EphA2 provides unextraordinary opportunity for antibody-based targeting of metastatic carcinoma. To test this, we recently used innovative strategies to generate antibodies against epitopes on the extracellular domain of EphA2. Here, we propose to develop new assay systems to test EphA2 as a target for monoclonal antibody treatment of metastatic cancer cells. Our Specific Aims are: i) to identify EphA2 antibodies that can target tumor cells, ii) to test if these antibodies block metastatic cell growth or invasiveness, and iii) to determine the mechanisms of antibody action. Upon conclusion of our studies, we will have validated EphA2 as a molecular target for cancer treatment and will have generated the reagents and expertise to exploit a critical vulnerability on malignant cells.

描述：（由申请人提供） 酪氨酸激酶活性水平的升高是生长和发育所必需的 恶性癌细胞的播散。我们实验室最近申请了 单克隆抗体生产新技术并确定了显着的 EphA2酪氨酸激酶的表达和功能的变化 恶性癌。 EphA2 在癌细胞中过度表达（50-500 折叠），在具有最高水平的 EphA2 细胞中始终发现 转移潜力。我们还表明 EphA2 过度表达会导致 转移潜力，但转移细胞的生长和侵袭性 可以通过激活细胞表面的 EphA2 来逆转。基于这些 结果，我们假设 EphA2 为 基于抗体的转移癌靶向。为了测试这一点，我们最近 使用创新策略来生成针对表位的抗体 EphA2 的胞外结构域。在此，我们建议 开发新的检测系统来测试 EphA2 作为单克隆抗体的靶标 治疗转移性癌细胞。我们的具体目标是： i) 确定 EphA2 抗体可以靶向肿瘤细胞，ii) 测试这些抗体是否 阻止转移细胞生长或侵袭，以及 iii) 确定 抗体作用机制。当我们的研究结束时，我们将有 验证 EphA2 作为癌症治疗的分子靶标，并将 生成了利用关键漏洞的试剂和专业知识 恶性细胞。