Targeting Transcriptional Repression in CLL

基因组沉默通过基因突变、缺失或表观遗传学在肿瘤发生中的作用 在包括慢性疾病在内的各种人类恶性肿瘤中，改变已经被越来越多地认识到 淋巴细胞白血病(CLL)。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，而且很容易 通过有针对性的治疗干预可以逆转。大量的初步数据表明，抑制作用 DNA甲基转移酶(DNA MET)和组蛋白脱乙酰酶(HDAC)的表达可导致沉默基因的重新表达 CLL细胞的基因和体外选择性细胞毒作用。这项建议的具体目的是1) 测定DNA MeT抑制剂地西他滨的最低有效药理剂量(MEPD) 与HDAC抑制剂丙戊酸联合治疗氟达拉滨难治性CLL，2)至 了解如何进行和解释详细的药代动力学和 作为地西他滨和丙戊酸MEPD发现研究的一部分进行的药效学分析 目标1中描述的酸，以及3)使用HDAC的新进度表执行I期试验 抑制物，脱脂肽，体内评价HDAC酶抑制和CD20，CD80，CD86， HLA-DR和c-flip的表达。这些目标中概述的详细的第一阶段试验将为申请者提供 在进行早期临床试验方面进行彻底的教育，由生物终点和 翻译研究。广泛的药代动力学和药效学分析将在体内验证 DNA耗竭，HDAC酶抑制，组蛋白H3和H4乙酰化，基因重新表达 化验，允许稍后将这项工作扩展到B细胞非霍奇金淋巴瘤。科学的财富 俄亥俄州立大学提供了关于人类恶性肿瘤表观遗传修饰的专业知识， 约翰·伯德和迈克尔·格雷弗博士的指导，他们是CLL发病机制和治疗方面公认的领导者， 克里斯托夫·普拉斯博士是研究人类恶性肿瘤异常DNA甲基化的专家，在他的指导下， 确保这项提议的成功。在这项资助的支持下，申请人将履行之前 描述I期试验，并通过NIH K30参加正式的教学临床研究人员培训- 俄亥俄州立大学提供资助的临床研究课程，长期目标是 成为一名独立资助的临床研究人员。

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 MeTinhibitor, 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.