Verteporfin as a YAP/TAZ inhibitor for treatment of glioblastoma
维替泊芬作为 YAP/TAZ 抑制剂治疗胶质母细胞瘤
基本信息
- 批准号:10737348
- 负责人:
- 金额:$ 57.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-21 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAdultAngiogenesis InhibitorsAnimal ModelApoptosisBindingBrainBrain NeoplasmsCell CommunicationCell DeathCell SurvivalCell physiologyCellsClinicalClinical TrialsDNADataDependenceDoseDrug TargetingEdemaEpidermal Growth Factor ReceptorEpigenetic ProcessFDA approvedFluorescence SpectrometryGene ExpressionGenesGeneticGenetic TranscriptionGlioblastomaGliomaGoalsGrowthHumanImmunocompetentImmunosuppressionLiposomesMacular degenerationMalignant - descriptorMalignant GliomaMalignant neoplasm of brainMalignant neoplasm of central nervous systemMass Spectrum AnalysisMediatingMetabolismModelingMusMutationNeoplasmsNeurogliaOncogenicOrganoidsPIK3CG genePathway interactionsPatientsPharmaceutical PreparationsPhase 0 Clinical TrialPhase I/II Clinical TrialPhosphotransferasesPrimary Brain NeoplasmsProcessProliferatingProteinsProto-Oncogene Proteins c-mycReceptor Protein-Tyrosine KinasesRecurrenceResistanceSignal PathwaySignal TransductionSpecimenStable DiseaseTestingTherapeuticTherapeutic EffectTranscription CoactivatorTranslational ResearchTumor PromotionTumor Stem CellsTumorigenicityVascular Endothelial Growth FactorsVerteporfinVisualizationXenograft Modelabsorptionangiogenesisbevacizumabblood-brain barrier crossingc-myc Genesclinical trial participantcofactorefficacy testingepigenomicsinhibitorinsightliposomal formulationmigrationmouse geneticsmouse modelmutantneoplastic cellnerve stem cellneuraloverexpressionpharmacologicpre-clinicalprogramsprotein expressionresponseresponse biomarkerself-renewalstem cell self renewalstem cellstherapeutic evaluationtherapeutic targettranscriptomicstumortumor diagnosistumor microenvironmenttumor progressionuptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Glioblastomas (GBMs), neoplasms composed of glial cells and their precursors, are among the deadliest primary
brain cancers, and are incurable with current therapies. There is an urgent unmet clinical need for new treatments
for GBM and related high-grade malignant gliomas. GBM tumorigenicity is often driven by genetic aberrations in
receptor tyrosine kinases (RTKs), such as EGFR, and the Pi-3 kinase (PI3K) signaling pathway. Through our
team’s collaborative translational research efforts, we discovered that the YAP and TAZ transcription co-
activators, effectors of the Hippo pathway that promote gene expression via TEAD co-factors, as key drivers of
GBM tumorigenicity downstream of oncogenic EGFR signaling. In testing YAP/TAZ function, our team
discovered that pharmacologic inhibition of YAP/TAZ with the FDA-approved drug verteporfin (VP) potently and
specifically provokes growth arrest and cell death of EGFR-mutant/amplified GBM cells, but spares normal
neural stem cells. VP inhibits YAP and TAZ by blocking their association with TEAD co-activators, which bind to
DNA. We found that VP specifically suppressed expression of YAP/TAZ transcriptional targets, including EGFR,
and that VP treatment conferred significant survival benefits in an orthotopic GBM xenograft model and a mouse
genetic GBM model. Our results led us to perform a phase 0 clinical trial of VP in patients with recurrent GBM,
which showed that VP is absorbed in GBM tumor cells and that VP induced changes consistent with inhibition
of YAP/TAZ function. Based on our results, we have initiated a phase 1/2 clinical trial of VP to determine optimal
dosing of VP in GBM patients. Here, we propose to investigate the therapeutic potential of YAP/TAZ inhibition
and to capitalize our VP clinical trials, we propose to Aim 1) Identify YAP/TAZ target genes that underlie the
epigenetic basis of YAP/TAZ dependency in GBM progression, Aim 2) Determine mechanisms of adaptation to
YAP/TAZ inhibition and verteporfin resistance in pre-clinical GBM models in order to identify epigenomic
adaptations specific that allow GBM stem cells to escape therapeutic targeting, and Aim 3) Evaluate the impact
of verteporfin combined with anti-angiogenic therapies on GBM stem cells and the tumor microenvironment in
immunocompetent mouse models and in specimens from human patients on our clinical trial of VP. The broader
goals of this project are to establish a basis and strategies for therapeutic targeting YAP/TAZ activity in GBM
using repurposed VP as a treatment for GBM.
项目总结/摘要
胶质母细胞瘤(GBM)是由胶质细胞及其前体组成的肿瘤,是最致命的原发性肿瘤之一。
脑癌,用目前的疗法是无法治愈的。临床急需新的治疗方法
用于GBM和相关的高级别恶性胶质瘤。GBM致瘤性通常由遗传畸变驱动,
受体酪氨酸激酶(RTK),如EGFR,和Pi-3激酶(PI 3 K)信号传导途径。通过我们
通过团队的合作翻译研究工作,我们发现雅普和TAZ转录共同作用,
激活剂,通过TEAD辅因子促进基因表达的Hippo途径的效应物,作为
致癌EGFR信号传导下游的GBM致瘤性。在测试雅普/TAZ功能时,我们的团队
发现FDA批准的药物维替泊芬(VP)有效地药理学抑制雅普/TAZ,
特异性地引起EGFR突变/扩增的GBM细胞的生长停滞和细胞死亡,但不影响正常的GBM细胞,
神经干细胞VP通过阻断雅普和TAZ与TEAD共激活剂的结合来抑制它们,TEAD共激活剂结合到
DNA.我们发现VP特异性抑制雅普/TAZ转录靶点的表达,包括EGFR,
并且VP治疗在原位GBM异种移植模型和小鼠中赋予显著的存活益处
遗传GBM模型我们的研究结果使我们在复发性GBM患者中进行了VP的0期临床试验,
这表明VP在GBM肿瘤细胞中被吸收,并且VP诱导的变化与抑制一致
雅普/TAZ功能。根据我们的研究结果,我们已经启动了VP的1/2期临床试验,以确定最佳的
GBM患者的VP给药。在这里,我们建议研究雅普/TAZ抑制的治疗潜力
为了利用我们的VP临床试验,我们建议目标1)鉴定雅普/TAZ靶基因,
GBM进展中雅普/TAZ依赖性的表观遗传学基础,目的2)确定适应的机制,
临床前GBM模型中的雅普/TAZ抑制和维替泊芬抗性,以鉴定表观基因组
特异性适应,允许GBM干细胞逃避治疗靶向,目的3)评估影响
维替泊芬联合抗血管生成疗法对GBM干细胞和肿瘤微环境的影响
免疫活性小鼠模型和来自人类患者的样本中的VP临床试验。更广泛的
本研究的目的是为GBM中的雅普/TAZ活性的靶向治疗建立基础和策略
用VP治疗GBM
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Renee D Read其他文献
Renee D Read的其他文献
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{{ truncateString('Renee D Read', 18)}}的其他基金
Human Organoid Models for Pediatric High-Grade Gliomas
儿童高级别胶质瘤的人体类器官模型
- 批准号:
10727450 - 财政年份:2023
- 资助金额:
$ 57.75万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10690229 - 财政年份:2022
- 资助金额:
$ 57.75万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10373782 - 财政年份:2021
- 资助金额:
$ 57.75万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10756382 - 财政年份:2021
- 资助金额:
$ 57.75万 - 项目类别:
MET kinase fusions in pediatric glioblastoma
儿童胶质母细胞瘤中的 MET 激酶融合
- 批准号:
10532158 - 财政年份:2021
- 资助金额:
$ 57.75万 - 项目类别:
Mechanisms of RIOK2 function in glioblastoma
RIOK2在胶质母细胞瘤中的功能机制
- 批准号:
10232051 - 财政年份:2017
- 资助金额:
$ 57.75万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8668168 - 财政年份:2012
- 资助金额:
$ 57.75万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8504550 - 财政年份:2012
- 资助金额:
$ 57.75万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
8450950 - 财政年份:2012
- 资助金额:
$ 57.75万 - 项目类别:
Revealing new regulators of EGFR-P13K driven glioma proliferation and migration
揭示 EGFR-P13K 驱动神经胶质瘤增殖和迁移的新调节因子
- 批准号:
7707429 - 财政年份:2009
- 资助金额:
$ 57.75万 - 项目类别:
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