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：
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
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/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

项目摘要

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基于令人鼓舞的临床试验，迫切需要有效治疗的毁灭性脑癌。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。然而，在过去的四十年里，GBM 的治疗得到了批准，而抗血管生成药物的初步反应却不尽如人意。治疗通常很重要，但这些药物对许多肿瘤的反应持续时间有限。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的作用比传统化疗通常出现的突变更容易产生变化本申请的目的是研究侵入性抗血管生成治疗的假设。耐药性是由上调受体酪氨酸激酶 c-Met 和 ¿ 之间的相互作用介导的1个整合素，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我们将在以下具体目标中研究这一假设：目标 1 - 确定趋化 c-Met 和触触性的机制 ¿ 1 整合素在抗血管生成后上调治疗；目标 2 - 检查 c-Met 和 ¿ 1个整合素相互作用促进侵袭和抗血管生成治疗耐药的肿瘤生长；目标 3 - 研究破坏 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对肿瘤体内侵袭性生长的影响或在获得抵抗力后，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该项目的成功完成可以（1）确定 VEGF 对粘连的影响。肿瘤侵袭；（2）确定对抗血管生成治疗的抵抗的中心机制，这也将有所帮助我们了解肿瘤如何适应缺氧；以及（3）确定针对侵袭性抵抗的药物；因此，我们希望这些研究能够深入了解抗血管生成疗法的双刃剑。通过揭示长期断流或 VEGF 阻断的不良反应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。