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（即组蛋白脱乙酰基化和DNA甲基化）在恶性细胞中肿瘤抑制基因异常沉默中起的作用已得到很好的确定。现在，人们普遍的共识是，异常的组蛋白脱乙酰化和DNA甲基化有助于AML的白血病。最近的研究集中在表观遗传转录沉默的分子基础上，支持核组蛋白以动态方式与DNA甲基化相互作用的概念，以抑制对造血分化和凋亡重要的基因。这些机制引起的基因组沉默可以通过组蛋白脱乙酰基酶（HDAC）和DNA甲基转移酶（DNMT）抑制剂来缓解。 AML中的临床前研究证明了这些药物的体外协同作用，从而提高了临床协同作用。然而，对于抑制特定的HDAC和DNMT酶亚型或酶抑制动力学的特异性，对此策略的特异性知之甚少，以及这与AML患者的临床益处之间的关系。因此，为了了解其全部潜力，需要在临床试验的背景下对HDAC和DNMT抑制剂引起的药理和生物学作用进行系统研究。在这里，我们建议探索与AML中组蛋白脱乙酰基化和DNA甲基化机制的抑制活性的抑制作用的组合。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，激活末端分化并降低白血病细胞中的凋亡阈值，从而引起临床益处。为了检验这些假设，我们的具体目的是1）使用影响DNA甲基化机制（即decitabine）和染色质结构（即丙丙酸）进行I阶段研究的AML研究； 2）对这些药物进行药代动力学和药效学研究，这些研究将允许药物血浆水平，染色质变化以及基因重新表达与毒性和疾病反应的相关性。