New Therapeutic Approaches for Stratified High-REST GBM Subtype

摘要[使用“Acrobat”(Acrobat)或“Scale：100%”(预览)打印以获得合适的字体大小(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，提示 治疗可以针对特定的亚型。然而，所有新诊断的GBM患者都要接受一种 类似的治疗方案，导致患者总体预后较差。基底膜肿瘤含有干细胞样细胞 (GSCs)有助于肿瘤的启动、生长和对标准护理替莫唑胺(TMZ)和 电离辐射(IR)。因此，GSC提供了一个很好的系统来研究GBM的生物学和 开发和评估针对基底膜的靶向治疗方法。我们的长远目标是发展机制- 以治疗为基础的方法，显著推进了对GBM患者的护理。我们实验室发现了 转录抑制物作为干细胞的启动子，因此是一个关键的致癌调节因子，在 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 高水平表达REST的GSCs(HR-GSCs)在分子和生物学上与肿瘤不同 GSC表达低水平的REST(LR-GSCs)。此外，具有HR肿瘤转录组的GBM患者 签名的患者比具有LR肿瘤签名的患者存活时间更短，这与我们对HR-GSC的结果相似 在小鼠模型中与LR-GSC肿瘤进行比较。这些研究表明，休息是一种潜在的治疗方法 靶点在HR-GBM肿瘤中。然而，对于分层的HR-GSC肿瘤，还没有针对REST的特异性治疗方法。 本项目的目标是利用小鼠颅内确定治疗HR-GSC肿瘤的方法 肿瘤模型。首先，在这里获得的信息将决定是否靶向HR-GBM肿瘤与休息- 特异性抑制剂REST-VP16是一种有价值的治疗HR-GBM的方法。第二，获取的信息 这将决定是否通过外切体靶向具有其余miR下游靶点的HR-GBM肿瘤- 介导式分娩将促进HR-GBM的治疗方法。第三，我们将确定潜在的 部分肿瘤治疗前后的调控网络变化和转录组特征 条件。这样的监管网络将提供有关依赖治疗的变化的信息 下游路径和目标。转录组签名可以用来衡量治疗情况 在临床环境中的进展。第四，我们将确定Exosome介导的归巢机制 向HR-肿瘤递送MIR。在这里获得的信息将有助于设计具有增强的 到HR-GBM的寻的能力。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，此类方法有限。

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.