Tumor cell and microenvironment changes causing antiangiogenic therapy resistance

项目摘要/摘要 抗血管生成疗法在治疗像胶质母细胞瘤(GBM)这样的恶性肿瘤方面大有可为。 毁灭性的脑癌，迫切需要有效的治疗。以鼓励临床试验为基础 结果，2009年，抗血管生成血管生成血管内皮生长因子中和抗体贝伐单抗成为第三个FDA- 在过去的40年里批准了对GBM的治疗。然而，虽然对抗血管生成药物的初步反应 治疗通常意义重大，这些药物的反应时间有限。许多肿瘤，在 最初的反应会产生获得性侵袭性抵抗，这是一种快速进展的状态，预后很差。 小鼠模型表明，抗血管生成治疗的抵抗可能反映了转录或翻译 比传统化疗通常产生的突变更容易产生的变化 抵抗。此应用程序的目标是调查侵入性抗血管生成治疗的假设 抗性是由上调的受体酪氨酸激酶c-Met和整合素之间的相互作用所介导的， 靶向这两个因子或其上游调节因子可以预防或克服治疗 抵抗。我们将在以下具体目标内调查这一假设：目标1-确定 抗血管生成后趋化性c-Met和Hapotatic？1整合素上调的机制 治疗；目标2-检查c-Met和整合素相互作用促进侵袭和 肿瘤生长对抗血管生成治疗耐药；以及目标3-研究c-Met的干扰影响 1整合素或其调节剂在抗血管生成治疗期间对肿瘤体内侵袭性生长的影响 在获得抵抗力之后。我们将使用独特的工具和在我的 实验室，包括抗血管生成治疗耐药的新的体内模型和创新的应用 光漂白后荧光恢复(FRAP)研究整合素迁移率与病灶周转的关系 有耐药性的粘连。该项目的成功完成可以(1)确定血管内皮生长因子对 肿瘤侵袭；(2)确定抵抗抗血管生成治疗的中心机制，这也将有助于 美国了解肿瘤一般如何适应低氧；以及(3)确定针对侵袭性抵抗的药物 抗血管生成治疗。因此，我们期待这些研究能让我们深入了解中国的双刃剑 通过揭示延长断流术或阻断血管内皮生长因子的不良反应来进行抗血管生成治疗；以及 最终可能使抗血管生成治疗实现其巨大的治疗前景。

PROJECT SUMMARY/ABSTRACT 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 ¿1 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 ¿1 integrin are upregulated following anti-angiogenic therapy; Aim 2 - Examine the mechanisms by which c-Met and ¿1 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 ¿1 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.