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.

项目概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获得FDA加速批准然而，尽管对抗血管生成治疗的最初反应通常是，重要的是，随后的随机试验表明这些药物的反应持续时间有限。许多肿瘤在最初做出反应后，会发展出获得性侵袭性抵抗，这是一种快速进展的状态，小鼠模型表明，对抗血管生成治疗的抵抗可能反映了预后不良。转录蛋白修饰比导致传统突变的突变更容易产生沿着这些思路，在过去四年的资助中，我们已经证明了这一点。贝伐单抗诱导的 VEGF 耗竭导致 GBM 细胞释放受体酪氨酸激酶 c-Met 和 β1 来自 VEGFR2 隔离的整合素，使这两种受体能够在由于更大的亲和力和 c-Met/β1 复合物，c-Met 将 α5 整合素从其 β1 结合位点取代与 α5β1 整合素相比，纤连蛋白的亲和力更高。为了推进这些发现，本次资助的目标是。更新是为了研究可以克服抗血管生成治疗的侵入性耐药性的假设我们将通过靶向 c-Met 和 β1 整合素之间的相互作用来研究这一假设。具体目标如下：目标 1 - 研究 VEGF 耗竭驱动 c-Met/β1 复合物的机制 - 贝伐珠单抗耐药性 GBM 介导的侵袭性；目标 2 – 确定 c-Met/β1 复合物是否会产生导致 GBM 中侵袭性贝伐珠单抗耐药的特定细胞骨架变化；和目标 3 - 识别我们将开展抑制贝伐珠单抗耐药 GBM 中 c-Met 和 β1 整合素结合的疗法。这些研究使用了我实验室开发的独特工具和创新，包括我们新颖的体内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治疗的 3D 生物工程系统我们的合作者创建的小分子抑制剂库将使用最新的工具进行分析。技术，包括 CRISPR 基因编辑和基于质谱的免疫沉淀蛋白质组学评估 c-Met-β1 结合的影响，该项目的成功完成将确定中心机制。长期 VEGF 耗竭逆转正常侵袭所驱动的抗血管生成治疗耐药性抑制 VEGF 的作用，并确定针对抗血管生成药物的侵袭性耐药的药物因此，我们希望这些研究能够深入了解抗血管生成这把双刃剑。通过揭示长期 VEGF 阻断的不良影响来进行治疗，并最终可能允许抗血管生成疗法以实现其巨大的治疗前景。

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）

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

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

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

Microarray Analysis in Glioblastomas.

DOI：
10.1007/7651_2015_245
发表时间：
2016
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Bhawe, Kaumudi M;Aghi, Manish K
通讯作者：
Aghi, Manish K

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

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.

Incorporating Tumor-Associated Macrophages into Engineered Models of Glioma.