Pharmacologic modulation of chromatin remodeling in leu*

leu* 染色质重塑的药理学调节

• 批准号: 7096021
• 负责人: GUIDO MARCUCCI
• 金额: $ 25.95万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096021
• 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）：翻译后组蛋白修饰异常（即赖氨酸残基脱乙酰化/甲基化）似乎通过破坏基因表达并导致血肿细胞中细胞生长，分化和凋亡的异常模式在白血病发生中具有重要作用。与结构异常（即染色体缺失或基因突变）相反，导致基因功能不可逆转的丧失，通过组蛋白脱乙酰基酶（HDAC）抑制剂，可以通过这些机制诱导的基因组沉默来缓解这些机制。最近，我们进行了临床前研究，证明了这些药物在基因重新表达，造血分化和髓样和淋巴白血病细胞中凋亡的活性。这些研究导致了从实验室将这种治疗策略转化为急性髓样白血病（AML）和慢性淋巴细胞性白血病（CLL）（即OSU 0051和OSU 0336）的临床试验。尽管我们在AML和CLL患者中都证明了Depsipeptide（FR228）的体内生物学和临床活性（FR228），在OSU 0051上接受了每周药物管理治疗的AML和CLL患者，随后进行了一周的休息，然后在治疗和副作用之间再生长，例如长期疲劳，厌食症和Nausea的副作用。由于白血病中二肽的治疗潜力是显着的，并且尚未得到充分探讨，因此，我们建议使用在21天周期中第1、3、5、5天进行治疗的更剂量密集型，缩写的时间表。在当前的建议中，我们寻求：1）定义使用此新时间表在AML和CLL中管理Depspephetide的可行性； 2）评估二肽的药代动力学（PK），并将其与药效学（PD）和临床结果相关联； 3）测量与二肽的生物学活性相关的PD终点（即，抑制HDAC酶活性，组蛋白翻译后修饰，基因重新表达，细胞表面抗原调节和凋亡常见途径的激活）。还将研究通过MDR1和BCL-2家族成员的过表达介导对深度肽的抗性的潜在机制。我们研究的最终目标是建议在AML和CLL中进行随后的II期研究耐受性和生物活性剂量。此外，我们认为该时间表适合将来基于组合的方法。