Targeted Intervention Against EphA2 on Cancer Cells

描述：(申请人提供) 酪氨酸激酶活性水平的提高是生长和 恶性癌细胞的扩散。我们实验室最近申请了 新技术在单抗生产和鉴定中的应用 大鼠脑内EphA2酪氨酸激酶表达和功能的变化 恶性肿瘤。EphA2在癌细胞中过度表达(50-500 折叠)，EphA2的最高水平持续存在于 转移潜能。我们还展示了EphA2的过度表达 转移潜能，但转移细胞的生长和侵袭力 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 以抗体为基础的转移性肿瘤靶向研究。为了测试这一点，我们最近 使用创新策略生成针对表位的抗体 EphA2的胞外区。在此，我们建议 开发新的检测系统以检测EphA2作为单抗的靶标 转移癌细胞的治疗。我们的具体目标是：i)确定 可靶向肿瘤细胞的EphA2抗体，II)检测这些抗体是否 阻断转移性细胞生长或侵袭性，以及iii)确定 抗体作用的机制。在我们的研究结束后，我们将拥有 验证了EphA2作为癌症治疗的分子靶点，并将 生成了利用关键漏洞的试剂和专业知识 恶性细胞。

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.