Targeting Transcriptional Repression in CLL

针对 CLL 的转录抑制

基本信息

  • 批准号:
    7437362
  • 负责人:
  • 金额:
    $ 13.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
基因组沉默通过基因突变、缺失或表观遗传对肿瘤发生的贡献

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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KRISTIE A BLUM其他文献

KRISTIE A BLUM的其他文献

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{{ truncateString('KRISTIE A BLUM', 18)}}的其他基金

Dual targeting of XPO1 and BTK in B cell malignancies
B 细胞恶性肿瘤中 XPO1 和 BTK 的双重靶向
  • 批准号:
    8913541
  • 财政年份:
    2015
  • 资助金额:
    $ 13.51万
  • 项目类别:
Development of a comprehensive research program in mantle cell lymphoma in the ibrutinib era
伊布替尼时代套细胞淋巴瘤综合研究计划的制定
  • 批准号:
    9751793
  • 财政年份:
    2015
  • 资助金额:
    $ 13.51万
  • 项目类别:
OSU as Network Lead Academic Participating Site for the NCI NCTN
OSU 作为 NCI NCTN 网络主导学术参与网站
  • 批准号:
    8846076
  • 财政年份:
    2014
  • 资助金额:
    $ 13.51万
  • 项目类别:
Modulating the tumor micro-environment in CLL using flavopiridol and lenalidomide
使用黄酮吡醇和来那度胺调节 CLL 中的肿瘤微环境
  • 批准号:
    7529237
  • 财政年份:
    2008
  • 资助金额:
    $ 13.51万
  • 项目类别:
Modulating the tumor micro-environment in CLL using flavopiridol and lenalidomide
使用黄酮吡醇和来那度胺调节 CLL 中的肿瘤微环境
  • 批准号:
    7658285
  • 财政年份:
    2008
  • 资助金额:
    $ 13.51万
  • 项目类别:
Targeting Transcriptional Repression in CLL
针对 CLL 的转录抑制
  • 批准号:
    7683783
  • 财政年份:
    2005
  • 资助金额:
    $ 13.51万
  • 项目类别:
Targeting Transcriptional Repression in CLL
针对 CLL 的转录抑制
  • 批准号:
    6918859
  • 财政年份:
    2005
  • 资助金额:
    $ 13.51万
  • 项目类别:
Targeting Transcriptional Repression in CLL
针对 CLL 的转录抑制
  • 批准号:
    7067579
  • 财政年份:
    2005
  • 资助金额:
    $ 13.51万
  • 项目类别:

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研究组蛋白乙酰化在基因组组织和白血病发生中的功能
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