Tumor cell and microenvironment changes causing antiangiogenic therapy resistance

描述（由申请人提供）：抗血管生成疗法对恶性肿瘤的治疗有很大的希望，如胶质母细胞瘤（GBM），一种急需有效治疗的毁灭性脑癌。基于令人鼓舞的临床试验结果，2009年，抗血管生成vegf中和抗体贝伐单抗成为过去40年来fda批准的第三种GBM治疗药物。然而，虽然抗血管生成治疗的初始反应通常是显著的，但这些药物的反应持续时间有限。许多肿瘤在最初有反应后，发展为获得性侵袭性耐药，这是一种迅速进展的状态，预后较差。小鼠模型表明，抗血管生成治疗的耐药性可能反映了转录或翻译的变化，这些变化比传统化疗耐药性通常产生的突变更容易产生。本申请的目的是研究侵袭性抗血管生成治疗耐药是由上调的受体酪氨酸激酶c-Met和ß1整合素之间的相互作用介导的假设，并且靶向这两个因子或其上游调节因子可以预防或克服治疗耐药。我们将在以下具体目标中研究这一假设：目标1 -确定抗血管生成治疗后趋化c-Met和趋化ß1整合素上调的机制；目的2 -研究c-Met和ß1整合素相互作用促进抗血管生成治疗肿瘤侵袭和生长的机制；目的3：研究破坏c-Met和ß1整合素或其调节因子对肿瘤在抗血管生成治疗期间或获得性耐药后体内侵袭性生长的影响。我们将使用我的实验室开发的独特工具和创新来开展这些研究，包括抗血管生成治疗耐药性的新型体内模型和光漂白后荧光恢复（FRAP）的创新应用，以将局灶粘连中的整合素迁移和周转与耐药性联系起来。本课题的成功完成可以(1)明确VEGF对肿瘤侵袭的影响；(2)明确抗血管生成治疗抵抗的主要机制，这也将有助于我们了解肿瘤如何适应缺氧；(3)确定靶向抗血管生成治疗侵袭性耐药的药物。因此，我们期望这些研究通过揭示长时间断流或VEGF阻断的不良影响，为抗血管生成治疗的双刃剑提供洞察，并最终使抗血管生成治疗实现其巨大的治疗前景。

DESCRIPTION (provided by applicant): Anti-angiogenic therapy holds much promise for the treatment of malignancies like glioblastoma (GBM), a devastating brain cancer for which effective treatments are badly needed. Based on encouraging clinical trial results, in 2009, the anti-angiogenic VEGF-neutralizing antibody bevacizumab became just the third FDA-approved treatment for GBM in the past four decades. However, while the initial responses to anti-angiogenic therapy are often significant, these agents have had limited durations of response. Many tumors, after responding initially, develop acquired invasive resistance, a rapidly progressive state with a poor prognosis. Mouse models suggest that resistance to anti-angiogenic therapy likely reflects transcriptional or translational changes that are more readily generated than the mutations that typically arise with traditional chemotherapy resistance. The goal of this application is to investigate the hypothesis that invasive anti-angiogenic therapy resistance is mediated by an interaction between upregulated receptor tyrosine kinase c-Met and ß1 integrin, and that targeting these two factors or their upstream regulators can prevent or overcome therapeutic resistance. We will investigate this hypothesis within the following Specific Aims: Aim 1 - Determine the mechanisms by which chemotactic c-Met and haptotactic ß1 integrin are upregulated following anti-angiogenic therapy; Aim 2 - Examine the mechanisms by which c-Met and ß1 integrin interact to promote invasion and growth of tumors resistant to anti-angiogenic therapy; and Aim 3 - Investigate the impact of disrupting c-Met and ß1 integrin or their regulators on the in vivo invasive growth of tumors during anti-angiogenic therapy or after acquired resistance. We will carry out these studies using unique tools and innovations developed in my lab, including novel in vivo models of anti-angiogenic therapy resistance and an innovative application of fluorescence recovery after photobleaching (FRAP) to correlate integrin mobility and turnover in focal adhesions with drug resistance. Successful completion of this project could (1) define the effects of VEGF on tumor invasion; (2) define central mechanisms of resistance to anti-angiogenic therapy, which would also help us understand how tumors adapt to hypoxia in general; and (3) identify agents targeting invasive resistance to anti-angiogenic therapy. Therefore, we expect these studies to offer insight into the double-edged sword of anti-angiogenic therapy by revealing adverse effects of prolonged devascularization or VEGF blockade, and could ultimately allow anti-angiogenic therapy to fulfill its tremendous therapeutic promise.