Targeting epigenetic regulation to disrupt glioma stem cell maintenance.

针对表观遗传调控来破坏神经胶质瘤干细胞的维持。

• 批准号: 8784783
• 负责人: Tyler Eugene Miller
• 金额: $ 4.77万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784783
• 关键词: Adjuvant; Affect; Area; Arginine; Azacitidine; Biological Assay; Biology; Brain; Brain Neoplasms; Cell Death; Cell Maintenance; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical; Cytotoxic Chemotherapy; Data; Development; Disease; Drug resistance; Epigenetic Process; Excision; Failure; Feedback; Future; Gene Expression; Gene-Modified; Genes; Genetic Models; Glioblastoma; Glioma; Growth; Histology; Histone Deacetylase Inhibitor; Histones; Human; Hypoxia; In Vitro; Laboratories; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Modification; Molecular Target; Nature; Oligodendroglia; Outcome; Pathogenesis; Patients; Pharmacologic Substance; Phenocopy; Play; Proteins; RNA Interference; Radiation; Radiation therapy; Regulation; Regulator Genes; Reporting; Research; Resistance; Role; Solid Neoplasm; Stem cells; Technology; Testing; Therapeutic; Therapeutic Index; Translating; Transplantation; Tumor Angiogenesis; Type I Epithelial Receptor Cell; aggressive therapy; angiogenesis; anticancer research; base; cancer cell; cancer stem cell; cell type; chemotherapeutic agent; chemotherapy; clinically relevant; conventional therapy; design; drug development; empowered; experience; improved; in vivo; innovation; interest; killings; neoplastic; neoplastic cell; nerve stem cell; new therapeutic target; novel; outcome forecast; palliation; pre-clinical; programs; public health relevance; rapid growth; response; screening; self-renewal; small hairpin RNA; stem cell population; success; therapeutic target; treatment strategy; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Glioblastoma (GBM) ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding GBM genetics and modeling these tumors, and new targeted therapies are being tested. Unfortunately, these advances have not substantially translated into improved patient outcomes. Multiple chemotherapeutic agents and radiation therapy have been developed to kill cancer cells. However, the response to chemotherapy and radiation in GBM is modest. There is clearly an unmet clinical need to develop either a novel treatment strategy or an adjuvant strategy to enhance efficacy of existing treatments. While no single mechanism provides for the failure of current GBM therapies, several laboratories including our own have shown that GBM tumors contain stem cell-like cells termed cancer stem cells (CSCs). The cancer stem cell hypothesis posits that tumor cells are organized in a hierarchy with CSCs at the apex. CSCs are resistant to cytotoxic therapies (Bao et al. Nature 2006) and promote tumor angiogenesis (Bao et al. Cancer Research 2006) supporting a direct clinical relevance. Our group and others have shown that CSCs reside in specific functional niches in perivascular and hypoxic niches (Li et al. Cancer Cell 2009; Lathia et al. Cell Stem Cell 2010), and targeting these niches may disrupt tumor maintenance and therapeutic resistance. Notably, our group has found that the microenvironment directly reprograms differentiated tumor cells into CSCs through the induction of epigenetic regulators (Heddleston et al. Cell Death Diff. 2012). While several therapies targeting epigenetic regulation in cancer have long been developed and in the clinic (e.g. HDAC inhibitors and Azacitidine) there has been a renewed interest in targeting this class of molecules based on the large amount of accumulating evidence that epigenetic regulation plays a central role in many diseases, particularly cancer. Major pharmaceutical companies and research agencies have developed large programs to try to target these moecules. With this resurgence of epigenetic drug development and evidence that epigenetic regulation controls cell state, I set out to identify novel epigenetic targets that are critical regulators of the CSC state in GBM. I conducted a targeted RNAi screen that focused on histone demethylases, a key class of epigenetic modifying genes. As epigenetic modifications, and therefore cell state are at least partially determined by the microenvironment, I utilized state-of-the-art RNAi screening technology to conduct the screen in vivo in the presence of a functional orthotopic microenvironment. Out of 31 histone demethylase genes screened, three candidate targets were identified, and clinical survival and gene expression data supports their potential as therapeutic targets. How CSC and normal neural progenitor biology is affect by targeting these hits will now be evaluated.

描述(申请人提供)：胶质母细胞瘤(GBM)是人类最致命的癌症之一，传统的治疗方法只能提供姑息治疗。在理解GBM遗传学和对这些肿瘤进行建模方面已经取得了很大进展，新的靶向治疗正在测试中。不幸的是，这些进展并没有实质性地转化为改善患者的结果。已经开发出多种化疗药物和放射疗法来杀死癌细胞。然而，GBM对化疗和放疗的反应是温和的。显然，临床上需要开发一种新的治疗策略或辅助策略来提高现有治疗的疗效，这显然是一个尚未得到满足的临床需求。虽然没有单一的机制导致目前的GBM治疗失败，但包括我们自己在内的几个实验室已经表明，GBM肿瘤中含有被称为癌症干细胞(CSCs)的干细胞样细胞。癌症干细胞假说认为，肿瘤细胞是以CSCs为顶端的层级组织的。CSCs对细胞毒治疗具有抵抗力(Bao等人)。自然，2006)和促进肿瘤血管生成(Bao等人。癌症研究2006)支持直接的临床相关性。我们的团队和其他人已经证明，CSCs存在于血管周围和缺氧性利基中的特定功能利基中(Li等人。癌症细胞，2009年；Lathia等人。细胞干细胞2010)，靶向这些利基可能会破坏肿瘤的维持和治疗耐药。值得注意的是，我们的团队发现，通过表观遗传调节因子的诱导，微环境直接将分化的肿瘤细胞重新编程为CSCs(Heddleston等人)。细胞死亡不同。2012年)。虽然针对癌症的表观遗传调控的几种治疗方法早已被开发出来，并在临床上(如HDAC抑制剂和氮杂西汀)，但基于大量积累的证据表明表观遗传调控在许多疾病，特别是癌症中发挥核心作用，人们对这类分子的靶向重新产生了兴趣。大型制药公司和研究机构已经制定了大型计划，试图针对这些分子。随着表观遗传药物开发的复苏，以及表观遗传调控控制细胞状态的证据，我开始识别新的表观遗传靶点，这些靶点是GBM中CSC状态的关键调控因素。我进行了一次有针对性的RNAi筛选，重点是组蛋白去甲基酶，这是一类关键的表观遗传修饰基因。由于表观遗传修饰，因此细胞状态至少部分由微环境决定，我利用最先进的RNAi筛选技术在功能原位微环境存在的情况下进行体内筛选。在筛选的31个组蛋白去甲基酶基因中，确定了3个候选靶点，临床生存和基因表达数据支持它们作为治疗靶点的潜力。现在将评估针对这些命中的CSC和正常神经前体生物学是如何影响的。