Tumor cell and microenvironment changes causing antiangiogenic therapy resistance

肿瘤细胞和微环境变化导致抗血管生成治疗耐药

• 批准号: 8631906
• 负责人: Manish Aghi
• 金额: $ 34.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631906
• 关键词: Adhesions; Adverse effects; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Cells; Clinic; Clinical Trials; Data; Dependence; Drug resistance; FDA approved; Fluorescence Microscopy; Fluorescence Recovery After Photobleaching; Focal Adhesions; Genetic; Genetic Transcription; Glioblastoma; Goals; Growth; Hepatocyte Growth Factor; Hypoxia; In Vitro; Integrin Binding; Integrins; Knowledge; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Measures; Mediating; Mentors; Mining; Mutation; Nature; Pathway interactions; Patients; Phosphorylation; Post-Translational Protein Processing; Process; RNA Interference; Receptor Activation; Receptor Protein-Tyrosine Kinases; Research; Resistance; Resistance development; Resolution; Role; Technology; Therapeutic; Tissues; Tumor Biology; Tumor Cell Invasion; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; Xenograft Model; Xenograft procedure; angiogenesis; base; bevacizumab; chemotherapy; combat; effective therapy; follow-up; imaging modality; improved; in vivo; in vivo Model; innovation; insight; meetings; mouse model; neoplastic cell; neutralizing antibody; novel; novel strategies; outcome forecast; preclinical study; prevent; programs; public health relevance; receptor; resistance mechanism; response; stressor; tool; tumor; tumor growth; tumor microenvironment; tumor progression

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.

项目总结/摘要 抗血管生成疗法对于恶性肿瘤如胶质母细胞瘤（GBM）的治疗有很大的希望， 严重的脑癌，急需有效的治疗方法。基于令人鼓舞的临床试验 结果，在2009年，抗血管生成VEGF中和抗体贝伐单抗成为第三个FDA- 在过去的四十年里被批准用于GBM的治疗。然而，虽然抗血管生成药物的最初反应 虽然这些药物的治疗效果通常是显著的，但这些药物的反应持续时间有限。许多肿瘤， 如果一开始就有反应，就会产生获得性侵入性耐药，这是一种预后不良的快速进展状态。 小鼠模型表明，抗血管生成治疗的抗性可能反映了转录或翻译 这些变化比传统化疗通常产生的突变更容易产生 阻力本申请的目的是研究侵入性抗血管生成治疗 抗性是由上调的受体酪氨酸激酶c-Met和β 1整联蛋白之间的相互作用介导的， 靶向这两个因子或其上游调节因子可以阻止或克服治疗性疾病， 阻力我们将在以下具体目标中研究这一假设：目标1 -确定 趋化性c-Met和趋触性β 1整合素在抗血管生成后上调的机制 目的2 -检查c-Met和整合素1相互作用促进侵袭和转移的机制。 抗血管生成治疗的肿瘤生长;目的3 -研究干扰c-Met的影响 和1整合素或其调节剂在抗血管生成治疗期间对肿瘤的体内侵袭性生长的影响，或 获得性抵抗后我们将使用在我的国家开发的独特工具和创新来进行这些研究。 实验室，包括抗血管生成治疗抗性的新型体内模型和 光漂白后的荧光恢复（FRAP）与整合素迁移率和局灶性 耐药性粘连。成功完成该项目可以（1）确定VEGF对 肿瘤侵袭;（2）确定抗血管生成治疗抵抗的中心机制，这也将有助于 我们了解肿瘤一般如何适应缺氧;（3）确定靶向抗侵袭性的药物， 抗血管生成治疗因此，我们希望这些研究能够提供对双刃剑的洞察力， 通过揭示长期断流或VEGF阻断的不良反应进行抗血管生成治疗，以及 最终可以让抗血管生成疗法实现其巨大的治疗前景。