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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

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.

Incorporating Tumor-Associated Macrophages into Engineered Models of Glioma.