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

• 批准号: 10217265
• 负责人: Xing Fan
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217265
• 关键词: Acetylation; Achievement; Adult; Binding; Biological Process; Blood - brain barrier anatomy; Brain Neoplasms; C-terminal; CRISPR/Cas technology; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cells; Clinic; Clinical; Clinical Data; Combined Modality Therapy; DNA Methylation; Data; Development; Disease; Down-Regulation; Epigenetic Process; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Glioblastoma; Goals; HDAC4 gene; Histone Deacetylase; Human; In Vitro; Knock-out; Length; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microarray Analysis; Molecular; Mus; N-terminal; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacotherapy; Phase I Clinical Trials; Phase I/II Clinical Trial; Prognosis; Proteins; Publishing; Radiation therapy; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; System; Tertiary Protein Structure; Testing; Translating; Xenograft procedure; base; c-myc Genes; cancer stem cell; cancer therapy; chemotherapy; effective therapy; gamma secretase; histone modification; improved; in vivo; inhibitor/antagonist; innovation; medulloblastoma; notch protein; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; promoter; prospective; resistance gene; self-renewal; stem cells; stem-like cell; success; temozolomide; therapy resistant; treatment strategy

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.

标题：通过表观遗传重编程靶向胶质母细胞瘤干细胞 抽象的： 胶质母细胞瘤（GBM）是成人最常见的恶性脑肿瘤，临床效果不佳 结果。这种致命疾病的治疗一直缺乏革命性的改进 过去40年的疾病。任何可以显着延长患者整体寿命的治疗 生存时间超过三个月，这是迄今为止治疗GBM的最好成绩 采用手术、放射治疗和替莫唑胺，才算成功。我们的长期 长期目标是为这种致命疾病开发新的治疗策略。 GBM 癌症干- 最近，多个研究小组前瞻性地分离出类细胞（CSC），并显示出耐药性 常规放射治疗和化学治疗。靶向 CSC 治疗带来希望 脑肿瘤患者。 Notch 信号是一种发育信号通路，已被 发现在 GBM CSC 中激活。我们已经证明，Notch 抑制会消耗 GBM CSC 并延长颅内 GBM 异种移植小鼠的生存期。最近的一期临床试验 研究表明，四分之一的恶性胶质瘤患者病情稳定超过 Notch抑制剂治疗后四个月。然而，介导Notch的目标受到监管 GBM CSC 的自我更新在很大程度上是未知的。当 CSC 产生非 CSC 细胞时，主要 两者之间的区别在于表观遗传学调控的基因表达水平不同，例如 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 Notch 抑制剂处理的 GBM 神经球的微阵列分析表明，表观遗传 因子组蛋白脱乙酰酶 4 (DHAC4) 受 Notch 信号传导调节。此外，我们的 初步研究表明 HDAC4 是 GBM 神经球传播所必需的 体外和体内。为了制定新的目标来消耗 GBM CSC，当前的提案将 研究Notch调节HDAC4的分子机制及其对GBM的影响 CSC 及其转化应用。 在具体目标#1中，我们将定义不同蛋白质结构域的功能效应 GBM CSC 上的 HDAC4。 在具体目标#2中，我们将定义Notch和HDAC4相互作用对自我的作用。 GBM CSC 更新。 在具体目标 3 中，我们将检查 Notch 和 HDAC4 抑制疗法的组合 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 HDAC4 调节 GBM CSC 的自我更新并改善 GBM 治疗，同时也将具有临床作用 对癌症治疗的总体影响。