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.

关键抑癌基因的表观遗传转录沉默在许多恶性肿瘤中的作用已被证实 建立良好。导致这种转录沉默的分子机制已经开始被研究 过去几年的阐明，导致了 DNA 甲基化以动态相互作用的概念 使用核组蛋白以及基于 Brg1 和 hBrm 的 SWI/SNF 复合物来抑制或增强 转录。慢性淋巴细胞白血病（CLL）的临床前工作已经证明了这些机制 基因沉默实际上与临床相关，并且针对不止一种基因沉默机制 导致协同基因重新表达和伴随的细胞凋亡。其他研究表明 这些药物能够激活细胞凋亡的替代途径，而这些途径不常被利用 CLL 的化疗或免疫疗法，并上调细胞表面抗原，这些抗原是潜在的分子 治疗目标。该转化研究项目的总体假设是应用 针对染色质结构变化的表观遗传治疗将缓解异常转录 抑制肿瘤抑制基因，恢复细胞增殖、分化的正常模式 细胞凋亡，最终为 CLL 患者带来临床益处。对这些的理性评价 药物将需要详细研究这些药物在肿瘤样本和体内的一系列生物学效应。作为 根据审稿人的建议，我们的研究将仅关注 CLL。我们的数据支持详细 CLL 表观遗传学治疗的研究；此外，这种疾病提供了分离大量 治疗期间多个点血液中肿瘤细胞的数量。该提案的具体目标是： 1) 对患有以下疾病的患者进行缩肽联合利妥昔单抗的新方案的 l/ll 期研究 氟达拉滨难治性 CLL。这项研究将伴随着详细的机制研究来评估 组蛋白脱乙酰酶抑制的动力学、组蛋白脱乙酰酶抑制调节的靶标以及机制 对缩酚肽的耐药性。 2) 进行最低有效药理学剂量探索研究 对氟达拉滨难治性 CLL 患者先使用地西他滨，然后地西他滨联合丙戊酸，然后再进行 随机 II 期研究，以确定这两种治疗方法的临床和基因再表达功效 接近。 3) 作为目标的一部分，同时进行详细的药理学和药效学研究 2 临床试验。每一个目标的发展都在很大程度上依赖于基本的投入 科学项目，例如确定目标基因（特别是项目 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 介导本文提出的表观遗传学靶向疗法的生物学效应。此外，调查结果 从这个翻译导向的项目中衍生出来的成果已经为新的假设做出了贡献，并在 项目 2-5 中的实验室，如每个提案中所述。