Targeted Intervention Against EphA2 on Cancer Cells

EphA2对癌细胞的靶向干预

• 批准号: 6643496
• 负责人: DEBORAH W KNAPP
• 金额: $ 23.3万
• 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/6643496
• 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; 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：（申请人提供） 酪氨酸激酶活性水平升高是必要的生长和 传播恶性癌细胞。我们的实验室最近应用了 单克隆抗体产生的新技术，并确定了戏剧性的 Epha2酪氨酸激酶在表达和功能中的变化 恶性肿瘤。 Epha2在癌细胞中过表达（由50-500 折叠），在细胞上始终发现EPHA2的最高水平 转移潜力。我们还表明epha2过表达 转移潜力，但转移细胞的生长和侵入性 可以通过在细胞表面激活EPHA2来逆转。基于这些 结果，我们假设Epha2为不正当的机会提供了 基于抗体的转移性癌靶向。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的细胞外域。在这里，我们建议 开发新的测定系统以测试EPHA2作为单克隆抗体的靶标 转移性癌细胞的治疗。我们的具体目的是：i）确定 可以靶向肿瘤细胞的EPHA2抗体，ii）测试这些抗体是否存在 阻断转移性细胞生长或侵入性，iii）确定 抗体作用的机理。在我们的研究结束后，我们将 验证EPHA2是癌症治疗的分子靶标，将具有 产生了试剂和专业知识，以利用关键的漏洞 恶性细胞。