Pharmacologic modulation of chromatin remodeling in leu*

描述(由申请人提供)：异常的翻译后组蛋白修饰(即赖氨酸残基去乙酰化/甲基化)似乎通过扰乱基因表达而在白血病发生中发挥重要作用，从而导致造血细胞中细胞生长、分化和凋亡的异常模式。与导致基因功能不可逆转的结构异常(即染色体缺失或基因突变)不同，由这些机制引起的基因组沉默可以通过组蛋白脱乙酰酶(HDAC)抑制剂的药物调节来缓解。最近，我们进行了临床前研究，证实了这些药物在髓系和淋巴细胞性白血病细胞中的基因再表达、造血分化和凋亡方面的活性。这些研究已经将这一治疗策略从我们的实验室转化为急性髓系白血病(AML)和慢性淋巴细胞白血病(CLL)(即OSU 0051和OSU 0336)的临床试验。尽管我们展示了一种有效的HDAC抑制剂--去脂肽(FR228)在AML和CLL患者中的体内生物学和临床活性，这些患者在OSU 0051上每周给药，然后休息一周，但治疗之间的再生长以及慢性疲劳、厌食和恶心等副作用阻止了这一计划的进一步发展。由于去脂肽在白血病中的治疗潜力是显著的，而且还没有被充分开发，在这里，我们建议使用更密集的剂量，缩短的治疗方案，在21天周期的第1，3，5天给药。在目前的方案中，我们试图：1)确定在AML和CLL中使用该新方案的可行性；2)评估深肽的药代动力学(PK)，并将其与药效学(PD)和临床结果相关联；3)测量与深肽生物活性相关的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激活常见的凋亡途径)。此外，还将探讨MDR1和bcl2家族成员过表达介导耐药的可能机制。我们研究的最终目标是为AML和CLL的后续II期研究推荐一个耐受性和生物活性的去脂肽剂量。此外，我们认为，这一时间表适用于未来的基于组合的方法。

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.