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(申请人提供)：基因组沉默通过基因突变、缺失或表观遗传学改变在肿瘤发生中的作用已在包括慢性淋巴细胞白血病(CLL)在内的各种人类恶性肿瘤中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常见，并且很容易通过有针对性的治疗干预而逆转。大量的初步数据表明，抑制DNA甲基转移酶(DNA MET)和组蛋白脱乙酰酶(HDAC)可以导致沉默基因的重新表达，并在体外对CLL细胞产生选择性细胞毒作用。这项建议的具体目的是1)确定DNA MET抑制剂地西他滨与HDAC抑制剂丙戊酸联合应用于氟达拉滨耐药CLL患者的最低有效药理剂量(MEPD)；2)了解作为目标1中描述的地西他滨和丙戊酸寻找MEPD研究的一部分进行的详细药代动力学和药效学分析的传导和解释；以及3)使用HDAC抑制剂Desi肽的新时间表进行I期试验，体内评估HDAC酶抑制以及CD20、CD80、CD86、HLA-DR和c-flip的表达。在这些目标中概述的详细的第一阶段试验将为申请人提供进行由生物学终点和翻译研究支持的早期临床试验的彻底教育。广泛的药代动力学和药效学分析将在体内验证DNA MET耗竭、HDAC酶抑制、组蛋白H3和H4乙酰化以及基因再表达分析，从而允许稍后将这项工作扩展到B细胞非霍奇金淋巴瘤。俄亥俄州立大学在人类恶性肿瘤的表观遗传修饰方面拥有丰富的科学专业知识，约翰·伯德博士和迈克尔·格雷弗博士是CLL发病机制和治疗领域公认的领导者，克里斯托夫·普拉斯博士是人类恶性肿瘤异常DNA甲基化方面的专家，他们的指导将确保这项提案的成功。在这笔资金的支持下，申请者将进行前面描述的第一阶段试验，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人员培训，长期目标是成为一名独立资助的临床研究人员。