Clinical Investigation of Epigenetic Therapy

表观遗传治疗的临床研究

• 批准号: 6985999
• 负责人: JOHN C. BYRD
• 金额: $ 31.61万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985999
• 关键词: DNA methylation; amidohydrolases; antineoplastics; apoptosis; blood cells; cell membrane; cell proliferation; chemotherapy; chromatin; clinical research; clinical trials; epigenetics; gene induction /repression; gene targeting; genes; histones; immunotherapy; lead; monoclonal antibody; neoplasm /cancer; pharmacokinetics; quality of life; repression; role; surface antigens; tumor suppressor genes

The role of epigenetic transcriptional silencing of key tumor suppressor genes in many malignancies has been well established. The molecular mechanisms leading to this transcriptional silencing have begun to be lucidated over the last several years, leading to the concept that methylation of DNA interacts in a dynamic way with nuclear histones and Brg1- and hBrm-based SWI/SNF complexes to either repress or enhance transcription. Pre-clinical work in Chronic Lymphocytic Leukemia (CLL) has demonstrated these mechanisms of gene silencing are in fact clinically relevant, and that targeting more than one mechanism of gene silencing results in synergistic gene re-expression and concomitant apoptosis. Additional studies have demonstrated the ability of these agents to both activate alternative pathways of apoptosis not commonly utilized by chemotherapy or immunotherapy in CLL, and to up-regulate cell surface antigens that are potential molecular therapeutic targets. The overall hypothesis of this translational research Project is that application of epigenetic therapy targeting chromatin structure changes will relieve aberrant transcriptional repression of tumor suppressor genes, restore normal patterns of cell proliferation, differentiation and apoptosis, and ultimately result in clinical benefit to patients with CLL. The rational evaluation of these agents will require detailed study of the serial biologic effect of these agents in tumor samples and in vivo. As suggested by the reviewers, our research therefore will focus on CLL only. Our data support a detailed investigation of epigenetic therapy in CLL; furthermore, this disease provides the ability to isolate a large number of tumor cells from the blood at multiple points during treatment. The specific aims of this proposal are: 1) To perform a phase l/ll study of a novel schedule of depsipeptide combined with rituximab in patients with fludarabine-refractory CLL. This study will be accompanied by detailed mechanistic studies to assess the kinetics of histone deacetylase inhibition, targets modulated by histone deacetylase inhibition, and mechanisms of resistance to depsipeptide. 2) To perform a minimum effective pharmacologic dose-finding study of decitabine and then decitabine combined with valproic acid in fludarabine refractory CLL patients, followed by a randomized phase II study to determine the clinical and gene re-expression efficacy of these two therapeutic approaches. 3) To perform concurrent detailed pharmacologic and pharmacodynamic studies as part of the Aim 2 clinical trial. The development of each of these aims has been heavily dependent on the input of the basic science Projects, such as for the determination of target genes (particularly Projects 2 and 3), identification of histone modifications (Project 4), and importance of Brgland hBrm based SWI/SNF complexes (Project 5) in mediating the biologic effect of the epigenetically targeted therapies proposed herein. In addition, the findings derived from this translationally directed Project have already contributed to new hypotheses to be tested in the laboratory in Projects 2-5, as outlined in each of their proposals.

在许多恶性肿瘤中，关键肿瘤抑制基因的表观遗传转录沉默的作用一直是 良好。导致这种转录沉默的分子机制已经开始 在过去的几年中，它清除了，导致了以下概念，即DNA的甲基化在动态中相互作用 与核组蛋白以及基于BRG1和HBRM的SWI/SNF复合物一起使用的方式来抑制或增强 转录。慢性淋巴细胞性白血病（CLL）的临床前研究证明了这些机制 基因沉默实际上在临床上是相关的，并且针对多种基因沉默机制 导致协同基因重新表达和伴随凋亡。其他研究表明 这些药物既激活凋亡的替代途径的能力 CLL中的化学疗法或免疫疗法，并上调潜在的分子的细胞表面抗原 治疗靶标。这个翻译研究项目的总体假设是 靶向染色质结构变化的表观遗传疗法将缓解异常转录 抑制肿瘤抑制基因，恢复细胞增殖的正常模式，分化和 细胞凋亡，并最终为CLL患者带来临床益处。这些的合理评估 药物将需要详细研究这些药物在肿瘤样品和体内的串行生物学效应。作为 因此，审稿人建议，我们的研究仅专注于CLL。我们的数据支持详细的 研究CLL表观遗传疗法；此外，这种疾病提供了分离大的能力 在治疗过程中，血液中多点的肿瘤细胞数量。该提案的具体目的是： 1）在患者患者中，对新型二肽和利妥昔单抗的新型深度肽的时间表进行相位的L/LL研究 氟达拉滨侵犯的Cll。这项研究将伴随着详细的机理研究，以评估 组蛋白脱乙酰基酶抑制的动力学，由组蛋白脱乙酰基酶抑制和机制调节的靶标 对深肽的抗性。 2）进行最低有效的有效药理剂量调查研究 解替滨，然后在氟达拉滨难治性CLL患者中与丙戊酸结合，然后是A 随机II期研究确定这两种治疗性的临床和基因重新表达功效 方法。 3）作为目的的一部分，进行同时进行详细的药理学和药效研究 2临床试验。每个目标的发展都在很大程度上取决于基本的输入 科学项目，例如确定目标基因（尤其是项目2和3），鉴定 组蛋白修饰（项目4），以及基于BRGland HBRM的SWI/SNF复合物（项目5）的重要性 介导此处提出的表观遗传靶向疗法的生物学作用。此外，发现 从这个翻译指导的项目中得出的已经有助于在 在每个提案中概述的项目2-5中的实验室。