Targeting Glioblastoma Stem Cells through Epigenetic Reprogramming

通过表观遗传重编程靶向胶质母细胞瘤干细胞 摘要： 胶质母细胞瘤（GBM）是成人最常见的恶性脑肿瘤，临床表现差， 结果。在治疗这种致命的疾病方面， 40年来的疾病。任何可以显著延长患者总体 生存超过三个月，这是迄今为止治疗GBM的最佳成就， 使用手术、放射治疗和替莫唑胺，可以认为是成功的。我们长久以来- 长期目标是为这种致命疾病开发新的治疗策略。GBM癌干细胞- 最近，几个研究小组前瞻性地分离出了类CSCs， 传统的放射治疗和化疗。靶向CSC治疗带来了希望， 脑肿瘤患者Notch信号传导是一种发育信号传导途径， 发现在GBM CSC中被激活。我们已经证明，Notch抑制耗尽GBM CSC 并延长了携带颅内GBM异种移植物的小鼠的存活时间。最近的一期临床试验 一项研究表明，四分之一的恶性胶质瘤患者已经稳定了疾病超过 Notch抑制剂治疗后4个月。然而，介导Notch调节的靶点 GBM CSC自我更新在很大程度上是未知的。当CSC产生非CSC细胞时， 两者之间的差异是由表观遗传学调节的不同水平的基因表达， 如DNA甲基化和组蛋白修饰，包括乙酰化。我们的初步数据来自 对Notch抑制剂处理的GBM神经球的微阵列分析显示， 组蛋白去乙酰化酶4（DHAC 4）因子由Notch信号传导调节。而且我们的 初步研究表明，HDAC 4是GBM神经球繁殖所必需的， 体外和体内。为了开发新的目标来消耗GBM CSC，目前的提案将 研究Notch调节HDAC 4的分子机制及其对GBM的影响 CSCs及其翻译应用。 在具体的目标#1中，我们将定义不同蛋白质结构域的功能效应， GBM CSC上的HDAC 4。 在具体的目标#2中，我们将定义Notch和HDAC 4相互作用对自我调节的作用。 更新GBM CSC。 在具体目标#3中，我们将研究Notch和HDAC 4抑制疗法的组合 在GBM患者来源的原位异种移植物（PDX）中。 当前提案的成功不仅会发现表观遗传因子HDAC 4 调节GBM CSC的自我更新并改善GBM治疗，而且还将具有临床意义。 对癌症治疗的影响。

Title: Targeting Glioblastoma Stem Cells through Epigenetic Reprogramming ABSTRACT: Glioblastoma (GBM) is the most common malignant brain tumor in adult with poor clinical outcome. There has been a lack of revolutionary improvement in treatment of this deadly disease over the past 40 years. Any treatment that can significantly prolong patients' overall survival for more than three months, which is the best achievement so far to treat GBM when using surgery, radiation therapy and temozolomide, can be considered as a success. Our long- term goal is to develop novel therapeutic strategies for this lethal disease. GBM cancer stem- like cells (CSCs) were recently prospectively isolated by several groups and showed resistance to conventional radiation therapy and chemotherapy. Targeting CSCs therapy brings a hope for brain tumor patients. The Notch signaling is a developmental signaling pathway that has been found activated in GBM CSCs. We have demonstrated that Notch inhibition deplete GBM CSCs and prolong survival in mice bearing intracranial GBM xenografts. A recent Phase I clinical trial study shows that a quarter of malignant glioma patients have stabilized disease for more than four month after Notch inhibitor treatment. However, the targets that mediate Notch regulated GBM CSC self-renewal are largely unknown. As CSCs give rise to non-CSC cells, the major difference between the two is a different level of gene expression regulated by epigenetics, such as DNA methylation and histone modification, including acetylation. Our preliminary data from microarray analysis on Notch inhibitor treated GBM neurosphere showed that an epigenetic factor Histone deacetylase 4 (DHAC4) is regulated by Notch signaling. Furthermore, our preliminary studies showed that that HDAC4 is required for GBM neurosphere propagation in vitro and in vivo. In order to develop new targets to deplete GBM CSCs, the current proposal will examine the molecular mechanism by which Notch regulates HDAC4 and its impact on GBM CSCs, and its translational application. In specific Aim #1, we will define the functional effect of different protein domains of HDAC4 on GBM CSCs. In specific Aim #2, we will define the role of Notch and HDAC4 interaction on self- renewal of GBM CSCs. In specific Aim #3, we will examine a combination of Notch and HDAC4 inhibition therapy in GBM patient-derived orthotopic xenografts (PDXs). Successes in the current proposal will not only discover how an epigenetic factor HDAC4 regulates self-renewal of GBM CSCs and improve GBM treatment, but also will have a clinical impact on cancer therapy in general.