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.

项目概要/摘要 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 严重需要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中和抗体贝伐珠单抗成为FDA批准的第三种药物。 过去四十年批准的 GBM 治疗方法。然而，虽然对抗血管生成的最初反应 治疗通常很重要，但这些药物的反应持续时间有限。许多肿瘤，之后 最初反应，发展获得性侵袭性抵抗，这是一种快速进展的状态，预后不良。 小鼠模型表明对抗血管生成治疗的抵抗可能反映了转录或翻译 比传统化疗通常出现的突变更容易产生变化 反抗。本申请的目的是调查侵入性抗血管生成疗法的假设 耐药性是由上调受体酪氨酸激酶 c-Met 和 ¿1 整合素之间的相互作用介导的， 并且针对这两个因素或其上游调节因子可以预防或克服治疗 反抗。我们将在以下具体目标中研究这一假设： 目标 1 - 确定 抗血管生成后趋化 c-Met 和趋触 ¿1 整合素上调的机制 治疗;目标 2 - 检查 c-Met 和 ¿1 整合素相互作用促进侵袭和侵袭的机制 肿瘤生长对抗血管生成治疗有抵抗力；目标 3 - 调查破坏 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或期间对肿瘤体内侵袭性生长的影响 获得抵抗力后。我们将使用我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耐药性的新型体内模型和创新应用 光漂白后的荧光恢复（FRAP）与整合素迁移率和局部周转相关 粘连具有耐药性。该项目的成功完成可以 (1) 确定 VEGF 对 肿瘤侵袭； (2) 明确抗血管生成治疗耐药的中心机制，这也将有助于 我们了解肿瘤一般如何适应缺氧； (3) 确定针对侵袭性耐药的药物 抗血管生成治疗。因此，我们期望这些研究能够提供对双刃剑的洞察。 通过揭示长期断流或 VEGF 阻断的副作用来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。