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Targeting Transcriptional Repression in CLL

针对 CLL 的转录抑制

基本信息

批准号：
7437362
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
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

来源：
https://reporter.nih.gov/project-details/7437362
关键词：
Aberrant DNA Methylation Acetylation Achievement Apoptosis Apoptotic B lymphoid malignancy B-Cell NonHodgkins Lymphoma Biological Assay CASP8 and FADD-like apoptosis regulating protein CD80 gene Cells Chromatin Chronic Lymphocytic Leukemia Clinical Clinical Investigator Clinical Research Clinical Trials CpG Islands DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA methyltransferase inhibition Data Decitabine Decitabine/Valproic Acid Deletion Mutation Depsipeptides Development Dose Down-Regulation Drug Kinetics Education Educational Curriculum End Point Ensure Enzyme Inhibition Enzymes Epigenetic Process Evaluation Funding Future Gene Expression Gene Mutation Gene Silencing Gene Targeting Genes Genetic Transcription Genomics Goals Grant Growth HLA-DR Antigens Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone Deacetylation Histone H3 Histone deacetylase inhibition Histones Human Immunologics In Vitro Investigation Kinetics Lead MS4A1 gene Malignant Neoplasms Maximum Tolerated Dose Mentorship Methylation Modification Molecular Conformation Monoclonal Antibody Hu1D10 Mutation Neoplasm Metastasis Ohio Pathogenesis Patients Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phosphotransferases Post-Translational Protein Processing Promoter Regions Proteins Randomized Refractory Regulation Research Research Personnel Sampling Schedule Small-Cell Lymphoma Surface Testing Therapeutic Intervention Thinking Time Toxic effect Training Transcriptional Activation Translational Research Tumor Suppressor Genes United States National Institutes of Health Universities Up-Regulation Valproic Acid Work base cancer cell cytotoxicity enzyme activity fludarabine gene repression in vivo neoplastic novel pre-clinical programs promoter response rituximab success tumor tumorigenesis

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