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

基本信息

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
项目类别：
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

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

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项目摘要

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（由适用提供）：抗血管生成疗法对治疗恶性肿瘤（例如胶质母细胞瘤（GBM））的治疗有很大的希望，胶质母细胞瘤（GBM）是一种毁灭性的脑癌，对此非常需要有效治疗。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过去四十年中GBM的第三次FDA批准的治疗方法。但是，尽管对抗血管生成疗法的最初反应通常很重要，但这些药物的反应持续时间有限。许多肿瘤最初做出反应后，产生了获得性侵入性抗性，这是一种迅速进步的状态，进展较差。小鼠模型表明，对抗血管生成疗法的耐药性可能反映出转录或翻译变化比通常以传统化学疗法耐药性而产生的突变更容易产生。该应用的目的是研究以下假设：侵袭性抗血管生成疗法的抗性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，并且针对这两个因素或其上游调节剂可以预防或克服治疗抗性。我们将在以下具体目的中研究这一假设：目标1-确定抗血管生成治疗后趋化C-MET和触觉c-Met和触觉β1整合素的机制上调；目标2-检查C-MET和ß1整联蛋白相互作用以促进抗抗血管生成疗法的肿瘤的侵袭和生长的机制； AIM 3-研究破坏C-MET和ß1整联蛋白或其调节剂对抗血管生成治疗期间肿瘤的体内侵入性生长的影响。我们将使用实验室中开发的独特工具和创新进行这些研究，包括新型的抗血管生成疗法耐药性体内模型，以及光漂白后荧光恢复（FRAP）的创新应用，以将整联蛋白的迁移率和焦点粘附性与耐药性相关联。该项目的成功完成可以（1）定义VEGF对肿瘤侵袭的影响；（2）定义了对抗血管生成疗法的抗性的中心机制，这也将有助于我们了解肿瘤如何适应缺氧；（3）确定靶向抗抗血管生成疗法的药物。因此，我们希望这些研究通过揭示长时间的血管形成或VEGF封锁的不良反应来洞悉抗血管生成疗法的双刃剑，并最终可以允许抗血管生成疗法实现其巨大的治疗疗法。