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）：通过遗传突变，缺失或表观遗传学改变对肿瘤发生的贡献，在包括慢性淋巴细胞性白血病（CLL）在内的各种人类恶性肿瘤中已越来越多地识别出来。 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，并且可以通过有针对性的治疗干预措施来易于逆转。 广泛的初步数据表明，抑制DNA甲基转移酶（DNA MET）和组蛋白脱乙酰基酶（HDAC）可以导致体外CLL细胞的沉默基因和选择性细胞毒性的重新表达。 该提案的具体目的是1）确定DNA MET抑制剂Decitabine的最小有效的药理学剂量（MEPD），以及HDAC抑制剂丙戊酸，丙甲酰胺抑制剂，氟达拉滨 - 替代CLL，2），以了解详细的药物和解释的药物的传导和解释Decabine和AIM 1中描述的核酸和丙戊酸的MEPD调查研究，以及3）使用HDAC抑制剂Depsipeptide的新计划进行I期试验，并在体内评估HDAC酶抑制作用和CD20，CD20，CD80，CD80，CD86，CD86，HLA-DR和C-FLIP表达。 这些目标中概述的详细I期试验将为申请人提供彻底的教育，以传导生物终点和转化研究支持的早期临床试验。 广泛的药代动力学和药效学分析将在体内验证DNA遇到耗竭，HDAC酶抑制，组蛋白H3和H4乙酰化以及基因重新表达测定，以后允许将此工作扩展到B-Cell Non-Hodgkin的淋巴瘤。 关于人类恶性肿瘤的表观遗传学修改的丰富科学专业知识是俄亥俄州立大学的指导。约翰·伯德（John Byrd）和迈克尔·格雷弗（Michael Grever）是CLL发病机理和治疗领域的领导者，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议的成功。 在这笔赠款的支持下，申请人将通过NIH K30资助的临床研究课程进行正式教学临床研究者培训，并参与俄亥俄州立大学的正式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。