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
• 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
• 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' 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

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”(Acrobat) 或“比例：100%”（预览）打印] 以获得正确的字体大小 (11)] 胶质母细胞瘤 (GBM) 是一种致命的人类脑肿瘤，由多种分子亚型组成，表明 治疗可以针对特定的亚型。然而，所有新诊断的 GBM 患者都接受了治疗 相似的治疗方案，导致患者总体预后不佳。 GBM肿瘤含有干细胞样细胞 (GSC) 有助于肿瘤的发生、生长和对标准治疗替莫唑胺 (TMZ) 的耐药性 电离辐射（IR）。因此，GSC 提供了一个优秀的系统来研究 GBM 的生物学和 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—— 基于治疗方法显着改善 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 还调节 GBM 的肿瘤发生，并且肿瘤 表达高水平 REST 的 GSC（HR-GSC）在分子和生物学上与肿瘤不同 表达低水平 REST 的 GSC（LR-GSC）。此外，具有 HR 肿瘤转录组的 GBM 患者 特征比具有 LR 肿瘤特征的患者的生存期更短，类似于我们的 HR-GSC 结果 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 肿瘤的靶点。然而，对于分层 HR-GSC 肿瘤，尚无特定的 REST 治疗方法。 该项目的目标是确定使用小鼠颅内肿瘤治疗 HR-GSC 肿瘤的方法 肿瘤模型。首先，此处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-VP16 是 HR-GBM 的一种有价值的治疗方法。二、获取信息 这里将确定是否通过外泌体用 REST 下游 miR 靶点靶向 HR-GBM 肿瘤 介导的递送将促进 HR-GBM 的治疗方法。第三，我们要确定底层 经过或未经治疗的选定肿瘤的调控网络变化和转录组特征 状况。此类监管网络将提供有关治疗依赖性变化的信息 下游途径和目标。转录组特征可能有助于衡量治疗效果 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。此处获得的信息将有助于设计具有增强功能的外泌体 HR-GBM 的归航能力。因此，该项目有潜力产生一种新颖的、基于机制的 HR-GBM 亚型的治疗方法，但此类方法是有限的。