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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：
10199057
负责人：
Manish Aghi
金额：
$ 35.2万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199057
关键词：
3-Dimensional Accounting Actin-Binding Protein Adverse effects Affinity Angiogenesis Inhibitors Angiogenic Factor Antineoplastic Agents Automobile Driving Binding Binding Sites Biomedical Engineering Blocking Antibodies Brain Brain Neoplasms Cells Chemicals Chemoresistance Clinic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Dependence Dose Dot Immunoblotting Evolution Exhibits Fibroblasts Fibronectins Funding Genes Genetic Transcription Glioblastoma Goals Grant Growth Heterodimerization Hydrogels ITGA5 gene Immunoprecipitation Industry Integrin Binding Integrin alpha5beta1 Integrins KDR gene Libraries Ligands Link Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediating Modeling Morphology Mutation Myosin ATPase Nature Nutrient Pathway interactions Patients Post-Translational Protein Processing Process Prognosis Proteomics RNA Interference RNA Splicing Receptor Protein-Tyrosine Kinases Recurrence Regimen Resistance Site-Directed Mutagenesis Structure System Techniques Therapeutic Tissue Banks Tumor Cell Invasion Variant Vascular Endothelial Growth Factors Vascularization Work Xenograft Model angiogenesis base bevacizumab drebrins effective therapy extracellular high throughput screening improved in vivo Model innovation insight migration mouse model neoplastic cell neutralizing antibody novel nutrient deprivation prevent randomized trial receptor recruit resistance mechanism response small molecule inhibitor targeted agent targeted treatment three-dimensional modeling tool transcription factor translational study tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY 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 was granted accelerated FDA approval for recurrent GBM treatment. However, while the initial responses to anti-angiogenic therapy are often significant, subsequent randomized trials have shown that these agents have 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 post- transcriptional protein modifications that are more readily generated than the mutations that cause traditional chemotherapy resistance. Along these lines, during the past four years of funding, we have shown that bevacizumab-induced VEGF depletion causes GBM cells to release receptor tyrosine kinase c-Met and β1 integrin from VEGFR2 sequestration, enabling these two receptors to form a powerful structural complex in which c-Met displaces α5 integrin from its β1 binding site due to greater affinity and the c-Met/β1 complex exhibits increased affinity than α5β1 integrin for fibronectin. To advance these findings, the goal of this grant renewal is to investigate the hypothesis that invasive resistance to anti-angiogenic therapy can be overcome by targeting the interaction between c-Met and β1 integrin. We will investigate this hypothesis within the following Specific Aims: Aim 1 - Investigate mechanisms by which VEGF depletion drives c-Met/β1 complex- mediated invasiveness in bevacizumab-resistant GBM; Aim 2 – Determine if the c-Met/β1 complex gives rise to specific cytoskeletal changes that drive invasive bevacizumab resistance in GBM; and Aim 3 - Identify therapies that inhibit the binding of c-Met and β1 integrin in bevacizumab-resistant GBM. We will carry out these studies using unique tools and innovations developed in my lab, including our novel in vivo models of anti-angiogenic therapy resistance, along with 3D bioengineered systems for studies of tumor cell invasion and small molecule inhibitor libraries created by our collaborators. These tools will be analyzed using the latest techniques, including CRISPR gene editing and mass spectrometry-based immuno-precipitation proteomics to assess the impact of c-Met-β1 binding. Successful completion of this project would define central mechanisms of resistance to anti-angiogenic therapy driven by prolonged VEGF depletion reversing the normal invasion suppressing effects of VEGF and would 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 VEGF blockade, and could ultimately allow anti-angiogenic therapy to fulfill its tremendous therapeutic promise.

项目总结抗血管生成疗法在治疗像胶质母细胞瘤(GBM)这样的恶性肿瘤方面大有可为。毁灭性的脑癌，迫切需要有效的治疗。以鼓励临床试验为基础结果，2009年，抗血管生成血管生成血管内皮生长因子中和抗体贝伐单抗获得FDA加速批准批准复发的GBM治疗。然而，尽管对抗血管生成治疗的最初反应通常是随后的重要随机试验表明，这些药物的反应时间有限。许多肿瘤在最初有反应后，会产生获得性侵袭性耐药，这是一种快速进展的状态，具有预后不良。小鼠模型显示，对抗血管生成治疗的抵抗可能反映了比导致传统基因突变更容易产生的转录蛋白质修饰化疗耐药。按照这些思路，在过去四年的筹资期间，我们已经表明贝伐单抗诱导血管内皮生长因子缺失导致基底膜细胞释放受体酪氨酸激酶c-Met和β-1 来自VEGFR2的整合素，使这两个受体形成一个强大的结构复合体由于更强的亲和力和c-Met/α1复合体，哪种c-Met取代了β5整合素与其β1结合部位表现出比α5β1整合素更高的对纤维连接蛋白的亲和力。为了推进这些发现，这笔赠款的目标是更新是为了研究可以克服对抗血管生成治疗的侵袭性耐药性的假设通过靶向c-Met和β-1整合素之间的相互作用。我们将在目标1-研究血管内皮生长因子耗竭驱动c-Met/β-1复合体的机制目的2-确定c-Met/β-1复合体是否导致在GBM中驱动侵袭性贝伐单抗耐药的特定细胞骨架变化；以及Aim 3-鉴定抑制贝伐单抗耐药基底膜中c-Met和β1整合素结合的治疗。我们将开展这些研究使用了我实验室开发的独特工具和创新，包括我们新颖的活体模型抗血管生成治疗耐药性，以及用于研究肿瘤细胞侵袭和由我们的合作者创建的小分子抑制物库。这些工具将使用最新的技术，包括CRISPR基因编辑和基于质谱学的免疫沉淀蛋白质组学评估c-Met-β1结合的影响。这一项目的成功完成将确定中央机制延长血管内皮生长因子耗竭逆转正常侵袭所致的抗血管生成治疗的耐药性抑制血管内皮生长因子的作用，并将识别针对侵袭性抵抗的抗血管生成药物心理治疗。因此，我们期望这些研究能为我们深入了解抗血管生成这把双刃剑提供帮助。治疗通过揭示长时间阻断血管内皮生长因子的不良反应，并最终可能允许抗血管生成以实现其巨大的治疗承诺。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies.

胶质母细胞瘤中对流增强的递送：临床前和临床研究的综述。

DOI：
10.3171/2016.1.jns151591
发表时间：
2017-01
期刊：
Journal of neurosurgery
影响因子：
4.1
作者：
Jahangiri A;Chin AT;Flanigan PM;Chen R;Bankiewicz K;Aghi MK
通讯作者：
Aghi MK

Mouse models of glioblastoma for the evaluation of novel therapeutic strategies.

DOI：
10.1093/noajnl/vdab100
发表时间：
2021-01
期刊：
Neuro-oncology advances
影响因子：
0
作者：
Haddad AF;Young JS;Amara D;Berger MS;Raleigh DR;Aghi MK;Butowski NA
通讯作者：
Butowski NA

Sarcopenia Diagnosed Using Masseter Muscle Diameter as a Survival Correlate in Elderly Patients with Glioblastoma.

肌肉减少症使用咬肌直径诊断为胶质母细胞瘤患者的生存率相关。

DOI：
10.1016/j.wneu.2022.02.038
发表时间：
2022-05
期刊：
WORLD NEUROSURGERY
影响因子：
2
作者：
Morshed, Ramin A.;Young, Jacob S.;Casey, Megan;Wang, Elaina J.;Aghi, Manish K.;Berger, Mitchel S.;Hervey-Jumper, Shawn L.
通讯作者：
Hervey-Jumper, Shawn L.

Microarray Analysis in Glioblastomas.