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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：
10318992
负责人：
SADHAN MAJUMDER
金额：
$ 40.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
https://reporter.nih.gov/project-details/10318992
关键词：
Affect Biological Assay Biology Brain Neoplasms Caring Characteristics Clinical Development Gender Genes Glioblastoma Goals Growth Homing Human In Situ In Vitro Intracranial Neoplasms Ionizing radiation Laboratories Mass Spectrum Analysis Measures Mediating Membrane Proteins Mesenchymal Stem Cells Methods Modeling Molecular Mus Newly Diagnosed Oncogenic Parents Pathway interactions Patient-Focused Outcomes Patients Process Property Proteomics Publishing Radiation Regimen Resistance System Testing Therapeutic Transcription Repressor Tumor Subtype Tumor-Derived Tumorigenicity VP 16 Women&apos s Group base cancer stem cell conventional therapy design exosome experience experimental study gender difference inhibitor knock-down male medulloblastoma molecular subtypes mouse model neoplastic cell novel novel therapeutic intervention promoter small hairpin RNA standard of care stem cell exosomes stem cells stem-like cell targeted treatment temozolomide therapeutic target therapy resistant transcriptome transcriptome sequencing tumor tumor growth tumor initiation tumorigenesis tumorigenic

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.

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