PHARMACOLOGICAL MODULATION OF EPIGENETIC CHANTGES IN AML

AML 表观遗传变化的药理学调节

• 批准号: 6872881
• 负责人: GUIDO MARCUCCI
• 金额: $ 30.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872881
• 关键词: DNA methylation; acetylation; acute myelogenous leukemia; amidohydrolases; antineoplastics; apoptosis; carcinogenesis; chromatin; clinical research; clinical trial phase I; dosage; enzyme inhibitors; gene expression; gene induction /repression; histones; human subject; human therapy evaluation; methyltransferase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; patient oriented research; pharmacokinetics; posttranslational modifications; valproate

DESCRIPTION (provided by applicant): The role that epigenetic changes (i.e., histone deacetylation and DNA methylation) play in the aberrant silencing of tumor suppressor genes in malignant cells has been well established. There is now general consensus that both aberrant histone deacetylation and DNA methylation contribute to leukemogenesis in AML. Recent studies focused on the molecular basis of epigenetic transcriptional silencing support the concept that nuclear histones interact with DNA methylation in a dynamic way to repress genes important for hematopoietic differentiation and apoptosis. Genomic silencing induced by these mechanisms can be relieved by pharmacological modulation with histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. Preclinical work in AML has demonstrated in vitro synergy of these agents that raises the hope of clinical synergy. However, little is known about the specificity of this strategy for inhibiting specific HDAC and DNMT enzyme subtypes or the kinetics of enzyme inhibition and how this relates to clinic benefit in AML patients. Therefore, to understand their full potential, a systematic study of the pharmacological and biological effects induced by HDAC and DNMT inhibitors in the context of clinical trials is required. Here we propose to explore combination of agents with a demonstrated inhibitory activity to the histone deacetylation and DNA methylation machinery in AML. We hypothesize that the therapeutic application of these agents will restore normal patterns of gene expression, activate terminal differentiation and lower the apoptotic threshold in the leukemic cells, and thereby induce clinical benefit. To test these hypotheses, our specific aims are 1) to perform a phase I study in AML using agents that affect the DNA methylation machinery (i.e., decitabine) and chromatin structure (i.e., valproic acid); 2) to perform pharmacokinetic and pharmacodynamic studies of these agents that will allow correlations of drug plasma levels, chromatin changes and gene re-expression with toxicity and disease response.

描述（由申请人提供）：表观遗传变化（即组蛋白脱乙酰化和 DNA 甲基化）在恶性细胞中肿瘤抑制基因的异常沉默中所起的作用已经得到充分证实。现在人们普遍认为，异常的组蛋白脱乙酰化和 DNA 甲基化都会导致 AML 中的白血病发生。最近的研究集中在表观遗传转录沉默的分子基础上，支持这样的概念：核组蛋白与 DNA 甲基化以动态方式相互作用，以抑制对造血分化和细胞凋亡重要的基因。这些机制引起的基因组沉默可以通过组蛋白脱乙酰酶 (HDAC) 和 DNA 甲基转移酶 (DNMT) 抑制剂的药理学调节来缓解。 AML 的临床前工作已经证明了这些药物的体外协同作用，这提高了临床协同作用的希望。然而，人们对这种抑制特定 HDAC 和 DNMT 酶亚型的策略的特异性或酶抑制的动力学以及这与 AML 患者的临床获益有何关系知之甚少。因此，为了了解它们的全部潜力，需要在临床试验中对 HDAC 和 DNMT 抑制剂诱导的药理和生物学效应进行系统研究。在这里，我们建议探索对 AML 中组蛋白脱乙酰化和 DNA 甲基化机制具有抑制活性的药物组合。我们假设这些药物的治疗应用将恢复基因表达的正常模式，激活终末分化并降低白血病细胞的凋亡阈值，从而产生临床益处。为了检验这些假设，我们的具体目标是 1) 使用影响 DNA 甲基化机制（即地西他滨）和染色质结构（即丙戊酸）的药物进行 AML 的 I 期研究； 2) 对这些药物进行药代动力学和药效学研究，将药物血浆水平、染色质变化和基因重新表达与毒性和疾病反应联系起来。