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.

项目摘要抗血管生成疗法对治疗恶性肿瘤（例如GBM）的治疗有很大的希望毁灭性的脑癌迫切需要有效治疗。基于鼓励临床试验结果，在2009年，授予了抗血管生成的VEGF中和抗体贝伐单抗的抗体加速了FDA 批准复发性GBM治疗。但是，虽然对抗血管生成疗法的最初反应通常是随后的重要随机试验表明，这些药物的响应持续时间有限。许多肿瘤最初作出反应后，产生了获得的侵袭性抗性，这是一种快速进行的状态预后不良。小鼠模型表明，对抗血管生成疗法的抗性可能反映了转录蛋白修饰比引起传统的突变更容易产生化学疗法抗性。沿着这些线，在过去四年的资金中，我们已经表明贝伐单抗诱导的VEGF耗竭会导致GBM细胞释放受体酪氨酸激酶C-MET和β1 vegfr2 session的整合素，使这两个受体能够形成强大的结构复合物哪个C-MET由于更高的亲和力和C-MET/β1复合物而从其β1结合位点取代α5整合素与纤维蛋白的α5β1整合素相比，表现出的亲和力增加。为了推进这些发现，这笔赠款的目标更新是为了研究可以克服抗血管生成疗法的侵入性抗性的假设通过靶向C-MET和β1整合素之间的相互作用。我们将研究这一假设以下特定目的：目标1-研究VEGF耗竭驱动C-Met/β1复合物的机制。抗贝伐单抗的抗侵袭性耐药性GBM； AIM 2 - 确定C-Met/β1复合物是否产生特定的细胞骨架变化，使GBM中侵入性bevacizumab抗性；目标3-识别抑制贝伐单抗耐药GBM中C-MET和β1整合素的结合的疗法。我们将执行这些研究使用我的实验室中开发的独特工具和创新的研究，包括我们的小说在体内模型抗血管生成疗法耐药性，以及3D生物工程系统，用于研究肿瘤细胞浸润和由我们的合作者创建的小分子抑制剂库。这些工具将使用最新的技术，包括CRISPR基因编辑和质谱基于质谱的免疫蛋白质组学评估C-MET-β1结合的影响。该项目的成功完成将定义中心机制长期VEGF耗竭驱动的抗血管生成疗法的抵抗力反转正常入侵抑制VEGF的作用，并将确定靶向抗抗血管生成的抗侵袭性的药物治疗。因此，我们希望这些研究能够深入了解抗血管生成的双刃剑通过揭示长时间VEGF阻滞的不良反应来治疗，并最终允许抗血管生成履行其巨大疗法的疗法。

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.