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:
- 金额:$ 35.2万
- 依托单位:
- 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:
- 关键词:3-DimensionalAccountingActin-Binding ProteinAdverse effectsAffinityAngiogenesis InhibitorsAngiogenic FactorAntineoplastic AgentsAutomobile DrivingBindingBinding SitesBiomedical EngineeringBlocking AntibodiesBrainBrain NeoplasmsCellsChemicalsChemoresistanceClinicClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexDependenceDoseDot ImmunoblottingEvolutionExhibitsFibroblastsFibronectinsFundingGenesGenetic TranscriptionGlioblastomaGoalsGrantGrowthHeterodimerizationHydrogelsITGA5 geneImmunoprecipitationIndustryIntegrin BindingIntegrin alpha5beta1IntegrinsKDR geneLibrariesLigandsLinkMalignant NeoplasmsMalignant neoplasm of brainMass Spectrum AnalysisMediatingModelingMorphologyMutationMyosin ATPaseNatureNutrientPathway interactionsPatientsPost-Translational Protein ProcessingProcessPrognosisProteomicsRNA InterferenceRNA SplicingReceptor Protein-Tyrosine KinasesRecurrenceRegimenResistanceSite-Directed MutagenesisStructureSystemTechniquesTherapeuticTissue BanksTumor Cell InvasionVariantVascular Endothelial Growth FactorsVascularizationWorkXenograft Modelangiogenesisbasebevacizumabdrebrinseffective therapyextracellularhigh throughput screeningimprovedin vivo Modelinnovationinsightmigrationmouse modelneoplastic cellneutralizing antibodynovelnutrient deprivationpreventrandomized trialreceptorrecruitresistance mechanismresponsesmall molecule inhibitortargeted agenttargeted treatmentthree-dimensional modelingtooltranscription factortranslational studytumortumor growthtumor microenvironmenttumor 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:
- 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:
- 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:
- 影响因子:0
- 作者:Bhawe, Kaumudi M;Aghi, Manish K
- 通讯作者:Aghi, Manish K
Incorporating Tumor-Associated Macrophages into Engineered Models of Glioma.
- DOI:10.1016/j.isci.2020.101770
- 发表时间:2020-12-18
- 期刊:
- 影响因子:5.8
- 作者:Akins EA;Aghi MK;Kumar S
- 通讯作者:Kumar S
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:
- 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.
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Manish Aghi其他文献
Manish Aghi的其他文献
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{{ truncateString('Manish Aghi', 18)}}的其他基金
Retroviral RLI/4-1 BBL and RLI/FLT3L Combination Immunomodulatory Gene Therapy for Glioblastoma
逆转录病毒 RLI/4-1 BBL 和 RLI/FLT3L 联合免疫调节基因治疗胶质母细胞瘤
- 批准号:
10740288 - 财政年份:2023
- 资助金额:
$ 35.2万 - 项目类别:
Retroviral RLI immunomodulatory gene therapy for glioblastoma
逆转录病毒 RLI 免疫调节基因治疗胶质母细胞瘤
- 批准号:
10522026 - 财政年份:2022
- 资助金额:
$ 35.2万 - 项目类别:
Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems
使用区域活检引导的生物材料系统对胶质母细胞瘤侵袭进行建模和药物基因组筛选
- 批准号:
10474358 - 财政年份:2018
- 资助金额:
$ 35.2万 - 项目类别:
Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems
使用区域活检引导的生物材料系统对胶质母细胞瘤侵袭进行建模和药物基因组筛选
- 批准号:
10237253 - 财政年份:2018
- 资助金额:
$ 35.2万 - 项目类别:
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
- 批准号:
8631906 - 财政年份:2013
- 资助金额:
$ 35.2万 - 项目类别:
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
- 批准号:
9285850 - 财政年份:2013
- 资助金额:
$ 35.2万 - 项目类别:
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
- 批准号:
8739317 - 财政年份:2013
- 资助金额:
$ 35.2万 - 项目类别:
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
- 批准号:
9094722 - 财政年份:2013
- 资助金额:
$ 35.2万 - 项目类别:
Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors
表征和靶向招募血管周围祖细胞的肿瘤因素
- 批准号:
8287632 - 财政年份:2009
- 资助金额:
$ 35.2万 - 项目类别:
Characterizing and Targeting Tumoral Factors Recruiting Perivascular Progenitors
表征和靶向招募血管周围祖细胞的肿瘤因素
- 批准号:
8500475 - 财政年份:2009
- 资助金额:
$ 35.2万 - 项目类别:
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