Pharmacologic modulation of chromatin remodeling in leu*

leu* 染色质重塑的药理学调节

• 批准号: 6938239
• 负责人: GUIDO MARCUCCI
• 金额: $ 26.57万
• 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: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938239
• 关键词: BCL2 gene /protein; acute myelogenous leukemia; amidohydrolases; antineoplastics; apoptosis; chromatin; chronic lymphocytic leukemia; clinical research; clinical trial phase I; dosage; drug administration rate /duration; enzyme activity; enzyme inhibitors; histones; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; pharmacokinetics; posttranslational modifications

DESCRIPTION (provided by applicant): Abnormal posttranslational histone modifications (i.e., lysine residue deacetylation/methylation) appear to have a significant role in leukemogenesis by disrupting gene expression and thereby leading to abnormal patterns of cell growth, differentiation and apoptosis in hematopoietic cells. In contrast to structural abnormalities (i.e., chromosome deletions or gene mutations) that cause irreversible loss of gene function, genomic silencing induced by these mechanisms can be relieved by pharmacologic modulation with histone deacetylase (HDAC) inhibitors. Recently, we have conducted preclinical studies demonstrating the activity of these agents with respect to gene re-expression, hematopoietic differentiation and apoptosis in myeloid and lymphoid leukemia cells. These studies have led to the translation of this therapeutic strategy from our laboratories into clinical trials for acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) (i.e., OSU 0051 and OSU 0336). Although we demonstrated in vivo biological and clinical activity of depsipeptide (FR228), a potent HDAC inhibitor, in both AML and CLL patients treated with weekly drug administration on OSU 0051 followed by one week of rest, regrowth between treatments and side effects such as chronic fatigue, anorexia and nausea prevented further development of this schedule. As the therapeutic potentials of depsipeptide in leukemia are remarkable and have not been fully explored yet, here, we propose to use a more dose-intensive, abbreviated schedule with treatments administered on days 1, 3, 5 of 21-day cycles. In the current proposal, we seek to: 1) define the feasibility of administering depsipeptide in AML and CLL using this new schedule; 2) assess the pharmacokinetics (PK) of depsipeptide and correlate them with pharmacodynamic (PD) and clinical results; 3) measure PD endpoints relevant to the biological activity of depsipeptide (i.e., inhibition of HDAC enzymatic activity, induction of histone posttranslational modifications, gene re-expression, cell surface antigen modulation and activation of common pathways of apoptosis). The potential mechanisms that mediate resistance to depsipeptide by overexpression of MDR1 and bcl-2 family members will also be investigated. The ultimate goal of our study is to recommend a tolerable and biologically active dose of depsipeptide for subsequent Phase II studies in AML and CLL. Further, we believe that this schedule is amenable to future combination-based approaches.

描述（由申请人提供）：异常翻译后组蛋白修饰（即赖氨酸残基脱乙酰化/甲基化）似乎通过破坏基因表达并从而导致造血细胞中细胞生长、分化和凋亡的异常模式在白血病发生中发挥重要作用。与导致基因功能不可逆丧失的结构异常（即染色体缺失或基因突变）相反，这些机制引起的基因组沉默可以通过组蛋白脱乙酰酶（HDAC）抑制剂的药理学调节来缓解。最近，我们进行了临床前研究，证明了这些药物在骨髓和淋巴细胞白血病细胞的基因再表达、造血分化和细胞凋亡方面的活性。这些研究使我们实验室的这种治疗策略转化为急性髓系白血病 (AML) 和慢性淋巴细胞白血病 (CLL) 的临床试验（即 OSU 0051 和 OSU 0336）。尽管我们在 AML 和 CLL 患者中证明了缩酚肽 (FR228)（一种有效的 HDAC 抑制剂）的体内生物学和临床活性，这些患者在 OSU 0051 上每周给药一次，然后休息一周，但治疗之间的再生和慢性疲劳、厌食和恶心等副作用阻碍了这一方案的进一步发展。由于缩酚肽在白血病中的治疗潜力非常显着，并且尚未得到充分探索，因此，我们建议使用剂量强度更大、更简短的方案，在 21 天周期的第 1、3、5 天进行治疗。在当前的提案中，我们寻求：1）确定使用这个新的时间表在 AML 和 CLL 中使用缩酚肽的可行性； 2) 评估缩酚肽的药代动力学（PK）并将其与药效学（PD）和临床结果相关联； 3) 测量与缩酚肽生物活性相关的 PD 终点（即抑制 HDAC 酶活性、诱导组蛋白翻译后修饰、基因重新表达、细胞表面抗原调节和常见凋亡途径的激活）。还将研究通过 MDR1 和 bcl-2 家族成员过度表达介导缩酚肽耐药性的潜在机制。我们研究的最终目标是为后续 AML 和 CLL 的 II 期研究推荐一种可耐受且具有生物活性的缩酚肽剂量。此外，我们相信这个时间表适合未来基于组合的方法。