Pharmacologic modulation of chromatin remodeling in leu*

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由此导致造血细胞中细胞生长、分化和凋亡的异常模式而在白血病发生中起重要作用。与结构异常（即，染色体缺失或基因突变），这些机制诱导的基因组沉默可以通过用组蛋白脱乙酰酶（HDAC）抑制剂进行药理学调节来缓解。最近，我们已经进行了临床前研究，证明这些药物的活性与基因的重新表达，造血分化和细胞凋亡的骨髓和淋巴白血病细胞。这些研究已经导致这种治疗策略从我们的实验室转化为急性髓性白血病（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（FR 228）（一种有效的HDAC抑制剂）的体内生物学和临床活性，所述AML和CLL患者通过每周给药OSU 0051然后休息一周来治疗，但是治疗之间的再生长和副作用（如慢性疲劳、厌食和恶心）阻止了该方案的进一步发展。由于缩肽在白血病中的治疗潜力是显著的，并且尚未被充分探索，因此在此，我们建议使用更剂量密集的简化方案，在21天周期的第1、3、5天给予治疗。在目前的提案中，我们寻求：1）定义使用这种新的时间表在AML和CLL中施用缩肽的可行性; 2）评估缩肽的药代动力学（PK）并将其与药效学（PD）和临床结果相关联; 3）测量与缩肽的生物活性相关的PD终点（即，HDAC酶活性的抑制、组蛋白翻译后修饰的诱导、基因再表达、细胞表面抗原调节和常见凋亡途径的激活）。还将研究通过MDR 1和bcl-2家族成员的过表达介导对缩酚酸肽的抗性的潜在机制。我们研究的最终目标是为AML和CLL的后续II期研究推荐一个可耐受的和生物活性剂量的缩肽。此外，我们认为，这一时间表是服从未来的组合为基础的方法。

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.