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: 9094722
• 负责人: Manish Aghi
• 金额: $ 34.67万
• 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/9094722
• 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; HGF gene; Health; Hypoxia; In Vitro; Integrin Binding; Integrins; KDR gene; Knowledge; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Measures; Mediating; Mentors; Mining; Mutation; Nature; Outcome; Pathway interactions; Patients; Phosphorylation; Post-Translational Protein Processing; Process; Publishing; 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 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; receptor; resistance mechanism; response; stressor; targeted agent; targeted treatment; therapy resistant; tool; tumor; tumor growth; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：抗血管生成疗法对于治疗胶质母细胞瘤（GBM）等恶性肿瘤有很大希望，胶质母细胞瘤是一种破坏性脑癌，迫切需要有效的治疗。基于令人鼓舞的临床试验结果，2009 年，抗血管生成 VEGF 中和抗体贝伐珠单抗成为过去 40 年来 FDA 批准的第三种治疗 GBM 的药物。然而，虽然抗血管生成治疗的初始反应通常很显着，但这些药物的反应持续时间有限。许多肿瘤在最初产生反应后，会产生获得性侵袭性耐药，这是一种快速进展的状态，预后不良。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以下假设：侵入性抗血管生成治疗耐药性是由上调受体酪氨酸激酶 c-Met 和 ß1 整合素之间的相互作用介导的，并且针对这两个因子或其上游调节因子可以预防或克服治疗耐药性。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 和趋触 ß1 整合素上调的机制；目标 2 - 检查 c-Met 和 ß1 整合素相互作用促进抗血管生成治疗耐药的肿瘤侵袭和生长的机制；目标 3 - 研究在抗血管生成治疗期间或获得性耐药后破坏 c-Met 和 ß1 整合素或其调节因子对肿瘤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，以及光漂白后荧光恢复（FRAP）的创新应用，以将整合素迁移率和粘着斑的周转与耐药性相关联。该项目的成功完成可以（1）明确VEGF对肿瘤侵袭的影响； （2）定义抵抗抗血管生成治疗的核心机制，这也将有助于我们了解肿瘤如何适应缺氧； (3) 确定针对抗血管生成治疗的侵入性耐药的药物。因此，我们期望这些研究能够揭示长期断流或 VEGF 阻断的不良影响，从而深入了解抗血管生成治疗的双刃剑，并最终使抗血管生成治疗能够实现其巨大的治疗前景。