Targeted Intervention Against EphA2 on Cancer Cells

描述：（申请人提供） 酪氨酸激酶活性水平的升高是生长所必需的， 恶性癌细胞的扩散。我们的实验室最近申请了 单克隆抗体生产中的新技术， EphA 2酪氨酸激酶的表达和功能的变化， 恶性肿瘤EphA 2在癌细胞中过表达（50-500 倍），其中在具有以下特征的细胞上始终发现最高水平的EphA 2： 转移潜能我们还表明EphA 2过表达赋予了 但转移细胞的生长和侵袭性 可以通过在细胞表面激活EphA 2来逆转。基于这些 结果，我们假设EphA 2提供了不寻常的机会， 转移性癌的基于抗体的靶向。为了验证这一点，我们最近 使用创新的策略来产生针对 EphA 2的胞外结构域。在此，我们建议 开发新的分析系统，以测试EphA 2作为单克隆抗体的靶标 转移性癌细胞的治疗。我们的具体目标是：i）识别 ii）测试这些抗体是否能够靶向肿瘤细胞， 阻断转移性细胞生长或侵袭，和iii）确定 抗体的作用机制。研究结束后，我们将 验证EphA 2作为癌症治疗的分子靶点， 生成了试剂和专业知识，以利用 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.