Targeting Transcriptional Repression in CLL

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、缺失或表观遗传学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常见，并且很容易通过靶向治疗干预逆转。 大量的初步数据表明，DNA甲基转移酶（DNA MeT）和组蛋白脱乙酰酶（HDAC）的抑制可以导致沉默基因的重新表达和CLL细胞的体外选择性细胞毒性。 该提议的具体目的是1）确定DNA MeT抑制剂地西他滨与HDAC抑制剂丙戊酸组合在氟达拉滨难治性CLL患者中的最低有效药理学剂量（MEPD），2）了解作为MEPD一部分进行的详细药代动力学和药效学试验的实施和解释-目的1中描述的地西他滨和丙戊酸的发现研究，和3）使用HDAC抑制剂缩酚肽的新方案进行I期试验，体内评价HDAC酶抑制和CD 20、CD 80、CD 86、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由生物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耗竭、HDAC酶抑制、组蛋白H3和H4乙酰化以及基因再表达测定，从而允许以后将这项工作扩展到B细胞非霍奇金淋巴瘤。 俄亥俄州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CLL发病机制和治疗方面公认的领导者John Byrd和Michael Grever博士的指导下，以及在人类恶性肿瘤异常DNA甲基化方面的专家Christoph Plass博士的指导下，将确保该提案的成功。 在该资助的支持下，申请人将进行上述I期试验，并通过俄亥俄州州立大学提供的NIH K30资助的临床研究课程参加正式的教学式临床研究者培训，其长期目标是成为独立资助的临床研究者。

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.