Targeting Transcriptional Repression in CLL

针对 CLL 的转录抑制

• 批准号: 6918859
• 负责人: KRISTIE A BLUM
• 金额: $ 13.51万
• 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: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918859
• 关键词: DNA methylation; acetylation; amidohydrolases; antileukemic agent; biotechnology; chronic lymphocytic leukemia; clinical research; clinical trial phase I; combination chemotherapy; enzyme inhibitors; gene expression; gene induction /repression; gene targeting; genetic transcription; high performance liquid chromatography; human subject; human therapy evaluation; methylguanine DNA methyltransferase; neoplasm /cancer chemotherapy; pathologic process; pharmacokinetics; polymerase chain reaction; valproate; western blottings

DESCRIPTION (provided by applicant): The contribution of genomic silencing to tumorigenesis through genetic mutation, deletions, or epigenetic alterations has been increasingly recognized in a variety of human malignancies, including chronic lymphocytic leukemia (CLL). Epigenetic modifications, including DNA methylation and histone acetylation, appear to be much more common in B-cell malignancies than mutations or deletions, and are readily reversible by targeted therapeutic interventions. Extensive preliminary data has demonstrated that inhibition of DNA methyltransferase (DNA MeT) and histone deacetylase (HDAC) can lead to re-expression of silenced genes and selective cytotoxicity of CLL cells in vitro. The specific aims of this proposal are 1) To determine the minimally effective pharmacologic dose (MEPD) of the DNA MeT inhibitor, decitabine, in combination with the HDAC inhibitor, valproic acid, in patients with fludarabine-refractory CLL, 2) To attain an understanding of the conduction and interpretation of detailed pharmacokinetic and pharmacodynamic assays performed as part of the MEPD-finding study of decitabine and valproic acid described in Aim 1, and 3) To perform a phase I trial using a novel schedule of the HDAC inhibitor, depsipeptide, with in vivo evaluation of HDAC enzyme inhibition and CD20, CD80, CD86, HLA-DR, and c-FLIP expression. The detailed phase I trials outlined in these aims will provide the applicant with a thorough education in the conduction of early clinical trials supported by biologic endpoints and translational research. The extensive pharmacokinetic and pharmacodynamic analyses will validate in vivo the DNA MeT depletion, HDAC enzyme inhibition, histone H3 and H4 acetylation, and gene re-expression assays, permitting later expansion of this work to B-cell non-Hodgkin's lymphoma. The wealth of scientific expertise regarding epigenetic modifications in human malignancies available at The Ohio State University, the mentorship of Drs. John Byrd and Michael Grever, recognized leaders in CLL pathogenesis and therapy, and the mentorship of Dr. Christoph Plass, an expert in aberrant DNA methylation in human malignancies, will ensure the success of this proposal. With the support of this grant, the applicant will perform the previously described phase I trials and participate in formal didactic clinical investigator training through a NIH K30- funded Clinical Research Curriculum available at The Ohio State University, with the long-term goal of becoming an independently funded clinical investigator.

描述（由申请人提供）：在包括慢性淋巴细胞白血病（CLL）在内的多种人类恶性肿瘤中，基因组沉默通过基因突变、缺失或表观遗传改变对肿瘤发生的贡献已得到越来越多的认识。 表观遗传修饰（包括 DNA 甲基化和组蛋白乙酰化）在 B 细胞恶性肿瘤中似乎比突变或缺失更为常见，并且很容易通过靶向治疗干预来逆转。 大量初步数据表明，抑制DNA甲基转移酶（DNA MeT）和组蛋白脱乙酰酶（HDAC）可导致沉默基因的重新表达和体外CLL细胞的选择性细胞毒性。 该提案的具体目标是 1) 确定 DNA MeT 抑制剂地西他滨与 HDAC 抑制剂丙戊酸联合治疗氟达拉滨难治性 CLL 患者的最低有效药理学剂量 (MEPD)，2) 了解作为研究的一部分进行的详细药代动力学和药效学测定的进行和解释。 目标 1 和 3 中描述的地西他滨和丙戊酸的 MEPD 发现研究 使用 HDAC 抑制剂缩肽的新方案进行 I 期试验，并对 HDAC 酶抑制和 CD20、CD80、CD86、HLA-DR 和 c-FLIP 表达进行体内评估。 这些目标中概述的详细第一阶段试验将为申请人提供有关进行由生物学终点和转化研究支持的早期临床试验的全面教育。 广泛的药代动力学和药效学分析将在体内验证 DNA MeT 消耗、HDAC 酶抑制、组蛋白 H3 和 H4 乙酰化以及基因重新表达测定，从而允许这项工作随后扩展到 B 细胞非霍奇金淋巴瘤。 俄亥俄州立大学在人类恶性肿瘤表观遗传修饰方面拥有丰富的科学专业知识，在博士的指导下。 John Byrd 和 Michael Grever（CLL 发病机制和治疗领域公认的领导者）以及人类恶性肿瘤异常 DNA 甲基化专家 Christoph Plass 博士的指导将确保该提案的成功。 在这笔资助的支持下，申请人将进行之前描述的 I 期试验，并通过俄亥俄州立大学提供的 NIH K30 资助的临床研究课程参加正式的教学临床研究者培训，其长期目标是成为一名独立资助的临床研究者。