New Therapeutic Approaches for Stratified High-REST GBM Subtype
分层高休息 GBM 亚型的新治疗方法
基本信息
- 批准号:10532153
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectBiological AssayBiologyBrain NeoplasmsCaringCharacteristicsClinicalDevelopmentGenderGenesGlioblastomaGoalsGrowthHomingHumanIn SituIn VitroIntracranial NeoplasmsIonizing radiationLaboratoriesMass Spectrum AnalysisMeasuresMediatingMembrane ProteinsMesenchymal Stem CellsMethodsModelingMolecularMusNewly DiagnosedOncogenicParentsPathway interactionsPatient-Focused OutcomesPatientsPrintingProcessPropertyProteomicsPublishingRadiationRegimenRepressionResistanceRestSystemTestingTherapeuticTranscription RepressorTumor SubtypeTumor-DerivedTumorigenicityVP 16Women&aposs Groupcancer stem cellcomparison controlconventional therapydesignexosomeexperienceexperimental studygender differenceinhibitorknock-downmalemedulloblastomamolecular subtypesmouse modelneoplastic cellnovelnovel therapeutic interventionpromotersmall hairpin RNAstandard of carestem cell exosomesstem cellsstem-like celltargeted treatmenttemozolomidetherapeutic targettherapy resistanttranscriptometranscriptome sequencingtumortumor growthtumor initiationtumorigenesistumorigenic
项目摘要
Summary [Print using "Actual size" (Acrobat) or "Scale: 100%" (Preview)] for proper font size (11)]
Glioblastoma (GBM), a lethal human brain tumor, is made up of multiple molecular subtypes, suggesting that
therapy could be targeted to particular subtypes. Yet all newly diagnosed GBM patients are treated with a
similar therapeutic regimen, which results in overall poor patient outcomes. GBM tumors contain stem-like cells
(GSCs) that contribute to tumor initiation, growth, and resistance to standard-of-care temozolomide (TMZ) and
ionizing radiation (IR). Thus, GSCs present an excellent system in which to study the biology of GBM and
develop and evaluate targeted therapeutic approaches to GBM. Our long-term goal is to develop mechanism-
based therapeutic approaches to significantly advance the care of GBM patients. Our laboratory discovered
the transcriptional repressor REST as a stem cell promoter, and thus a critical oncogenic regulator, in
medulloblastoma. We and others discovered that REST also regulates oncogenesis in GBM and that tumors
with GSCs expressing high levels of REST (HR-GSCs) are molecularly and biologically distinct from tumors
with GSCs expressing low levels of REST (LR-GSCs). Further, GBM patients with an HR tumor transcriptome
signature have shorter survival than patients with an LR tumor signature, similar to our results with HR-GSC
versus LR-GSC tumors in mouse models. These studies have suggested that REST is a potential therapeutic
target in HR-GBM tumors. Yet there is no REST-specific therapeutic approach for stratified HR-GSC tumors.
The goal of this project is to determine therapeutic approaches for HR-GSC tumors using mouse intracranial
tumor models. First, information obtained here will determine whether targeting HR-GBM tumors with REST-
specific inhibitor, REST-VP16, is a valuable therapeutic approach for HR-GBM. Second, Information obtained
here will determine whether targeting HR-GBM tumors with REST downstream miR targets via exosome-
mediated delivery would promote therapeutic approaches for HR-GBM. Third, we will determine the underlying
regulatory network changes and transcriptome signatures in selected tumors with and without treatment
conditions. Such regulatory networks will provide information about changes in treatment-dependent
downstream pathways and targets. The transcriptome signatures could be useful to measure treatment
progression in a clinical setting. Fourth, we will determine the homing mechanism of Exosome-mediated
delivery of miRs to HR-tumors. Information obtained here will aid in designing exosomes with enhanced
homing capabilities to HR-GBM. Thus, the project has the potential to produce a novel, mechanism-based
therapeutic approach for the HR-GBM subtype, for which such approaches are limited.
摘要[使用“实际大小”(缩略图)或“比例:100%”(预览)打印,以获得适当的字体大小(11)]
胶质母细胞瘤(GBM)是一种致命的人脑肿瘤,由多种分子亚型组成,这表明,
治疗可以针对特定的亚型。然而,所有新诊断的GBM患者都接受了
相似的治疗方案,导致患者总体结局较差。GBM肿瘤含有干细胞样细胞
(GSC),其有助于肿瘤起始、生长和对标准护理替莫唑胺(TMZ)的抗性,以及
电离辐射(IR)。因此,GSC提供了一个研究GBM生物学的极好系统,
开发和评估GBM的靶向治疗方法。我们的长期目标是建立机制-
基于治疗方法,以显着推进GBM患者的护理。我们的实验室发现
转录抑制因子REST作为干细胞启动子,因此是关键的致癌调节因子,
髓母细胞瘤我们和其他人发现,REST也调节GBM中的肿瘤发生,
表达高水平REST的GSC(HR-GSC)在分子和生物学上与肿瘤不同
其中GSC表达低水平的REST(LR-GSC)。此外,具有HR肿瘤转录组的GBM患者
与我们HR-GSC的结果相似,LR肿瘤标记的患者的生存期比LR肿瘤标记的患者短
与小鼠模型中的LR-GSC肿瘤相比。这些研究表明,REST是一种潜在的治疗方法,
HR-GBM肿瘤中的靶点。然而,对于分层的HR-GSC肿瘤没有REST特异性治疗方法。
本项目的目的是确定HR-GSC肿瘤的治疗方法,
肿瘤模型首先,这里获得的信息将确定是否用REST靶向HR-GBM肿瘤。
特异性抑制剂REST-VP 16是HR-GBM有价值治疗方法。二、获得的信息
这里将确定是否通过外泌体靶向REST下游miR靶向HR-GBM肿瘤,
介导的递送将促进HR-GBM的治疗方法。第三,我们将确定
有和无治疗的选定肿瘤中的调控网络变化和转录组特征
条件这种调控网络将提供有关治疗依赖性的变化的信息。
下游途径和目标。转录组特征可能有助于衡量治疗
在临床环境中的进展。第四,我们将确定外泌体介导的归巢机制。
将miR递送至HR肿瘤。这里获得的信息将有助于设计具有增强的
HR-GBM的归航能力因此,该项目有可能产生一种新颖的,基于机制的
HR-GBM亚型的治疗方法,对于HR-GBM亚型,这些方法是有限的。
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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SADHAN MAJUMDER其他文献
SADHAN MAJUMDER的其他文献
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{{ truncateString('SADHAN MAJUMDER', 18)}}的其他基金
2023 Basic Mechanisms to Clinical Trials in Brain Tumors Gordon Research Conference
2023年脑肿瘤临床试验的基本机制戈登研究会议
- 批准号:
10751111 - 财政年份:2023
- 资助金额:
$ 40.5万 - 项目类别:
New Therapeutic Approaches for Stratified High-REST GBM Subtype
分层高休息 GBM 亚型的新治疗方法
- 批准号:
10318992 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
New Therapeutic Approaches for Stratified High-REST GBM Subtype
分层高休息 GBM 亚型的新治疗方法
- 批准号:
10088012 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated regulation of opioid receptors in chronic pain mouse models
慢性疼痛小鼠模型中阿片受体的 REST 介导调节
- 批准号:
9977491 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated regulation of opioid receptors in chronic pain mouse models
慢性疼痛小鼠模型中阿片受体的 REST 介导调节
- 批准号:
10205014 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
- 批准号:
10472694 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
- 批准号:
9901187 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
- 批准号:
10256781 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
REST-mediated epigenomic and transcriptomic signatures in neuropathic pain
REST 介导的神经病理性疼痛的表观基因组和转录组特征
- 批准号:
10022172 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Implications of a novel glioblastoma classification defined by miR-21-Sox2 status
由 miR-21-Sox2 状态定义的新型胶质母细胞瘤分类的意义
- 批准号:
8431523 - 财政年份:2012
- 资助金额:
$ 40.5万 - 项目类别:
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