Epigenetics and Epigenetic Therapy in AML

AML 的表观遗传学和表观遗传学治疗

基本信息

批准号：
7468676
负责人：
Jean-Pierre J. Issa
金额：
$ 19.62万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7468676
关键词：
Aberrant DNA Methylation Accounting Acute Acute Myelocytic Leukemia Address CMV promoter Caring Cell Line Cessation of life Clinical Clinical Trials Clonal Evolution Complement Conduct Clinical Trials Consolidation Therapy CpG Islands Cytotoxic Chemotherapy DNA DNA Methylation DNA Methylation Inhibition DNA Repair Gene Daily Decitabine Development Diagnosis Disease Disease remission Dose Drug Combinations Drug resistance Dysmyelopoietic Syndromes End Point Epigenetic Process Funding Gene Expression Gene Silencing Genes Goals Grant Green Fluorescent Proteins Histone Deacetylase Inhibitor Histone Deacetylation Histone deacetylase inhibition Hour Hypermethylation In Vitro Lead Libraries Maintenance Measures Medicine Methylation Modeling Modification Myeloid Leukemia Myeloproliferative disease Natural History Newly Diagnosed Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacodynamics Phenotype Play Preclinical Drug Evaluation Prognostic Factor Prognostic Marker RNA Randomized Randomized Clinical Trials Rate Recurrent disease Relapse Remission Induction Reporter Genes Resistance Role Series Small Interfering RNA Southwest Oncology Group Standards of Weights and Measures System Testing Therapeutic Translating Tumor Suppressor Genes Tumor Suppressor Proteins United States Food and Drug Administration University of Texas M D Anderson Cancer Center Validation abstracting base bisulfite chemotherapy clinically relevant cohort concept day demethylation design follow-up gene function improved in vivo inhibitor/antagonist leukemia neoplastic neoplastic cell novel strategies prevent research study response tool treatment duration tumor vector

项目摘要

DMA methylation and associated epigenetic changes lead to functional alterations in pathways that promote neoplastic development. Therapy targeting DMA methylation and histone deacetylation, another epigenetic modification, has shown activity in myeloid leukemias, and is now part of standard of care in patients with myelodysplastic syndrome (MDS). We have identified a DMA hypermethylation signature that characterizes young patients with acute myeloid leukemia (AML) who have a high cure rate following standard cytotoxic chemotherapy. This signature was independent of known prognostic factors and, if validated, would provide an important tool towards personalized therapy in AML. Separately and paradoxically, we have shown that progression in AML (diagnosis to relapse) and in MDS (MDS to AML) is also associated with the progressive acquisition of aberrant DNA methylation that, in this situation, predicts for a poor overall outcome. Finally, in proof-of-concept studies, we have shown that treatment with the DNA methylation inhibitor DAC results in tumor-suppressor gene demethylation and reactivation in AML and MDS, associated with a relatively high response rate that correlates with induction of gene expression of the P15 tumor-suppressor. Based on these observations, we hypothesize that DNA methylation profiling identifies a subset of young patients with AML who are curable with standard chemotherapy. We further hypothesize that DNA methylation, through separate genes, also contributes to clonal evolution in AML, leading to relapses with drug resistant phenotypes, and that DNA methylation inhibition in remission will delay or eliminate clonal evolution and disease relapse in some patients. Finally, we hypothesize that strategies aimed at enhancing pharmacologic epigenetic reactivation will translate into better therapies for myeloid malignancies. To test these hypotheses, we propose the following specific aims: (1) Retrospectively and prospectively validate and extend an epigenetic signature of curability in AML. (2) Conduct a randomized clinical trial of remission maintenance in AML using DAC. (3) Use a methylated and silenced GFP reporter gene selectable system to identify key pathways and pharmacologic combinations that lead to epigenetic reactivation in neoplastic cells. This project will provide new markers of prognosis in AML and new approaches to therapy that are based on incorporating epigenetic modulation into the standard of care of this disease. Lay abstract: DNA methylation is a tag attached to DNA that modifies gene function by preventing RNA formation. Decitabine, a drug that modifies DNA methylation is useful in leukemia. We propose to verify that DNA methylation can identify patients who are curable with chemotherapy. We also propose to use decitabine to prevent relapse in AML, and we will find drugs that boost the activity of decitabine and that can be introduced into clinical trials

DMA 甲基化和相关的表观遗传变化导致通路的功能改变，从而促进肿瘤的发展。针对 DMA 甲基化和组蛋白脱乙酰化（另一种表观遗传）的治疗修改，已显示出对骨髓性白血病的活性，现在已成为患有以下疾病的患者标准护理的一部分骨髓增生异常综合征（MDS）。我们已经确定了 DMA 超甲基化特征，其特征在于接受标准细胞毒性治疗后治愈率较高的年轻急性髓系白血病 (AML) 患者化疗。该签名独立于已知的预后因素，如果经过验证，将提供 AML 个性化治疗的重要工具。单独且矛盾的是，我们已经证明 AML（诊断到复发）和MDS（MDS 到 AML）的进展也与进展相关。获得异常的 DNA 甲基化，在这种情况下，预示着总体结果不佳。最后，在概念验证研究表明，使用 DNA 甲基化抑制剂 DAC 进行治疗会导致 AML 和 MDS 中肿瘤抑制基因去甲基化和重新激活，与相对较高的反应率与 P15 肿瘤抑制基因表达的诱导相关。基于根据这些观察结果，我们假设 DNA 甲基化谱鉴定出一部分年轻患者可通过标准化疗治愈的 AML。我们进一步假设 DNA 甲基化通过单独的基因，也有助于 AML 的克隆进化，导致耐药性复发表型，并且缓解期的 DNA 甲基化抑制将延迟或消除克隆进化，部分患者病情复发。最后，我们假设旨在增强药理学的策略表观遗传再激活将转化为更好的骨髓恶性肿瘤治疗方法。为了检验这些假设，我们提出以下具体目标：（1）回顾性和前瞻性地验证和扩展 AML 治愈性的表观遗传特征。 (2) 进行缓解维持的随机临床试验使用 DAC 的 AML。 (3) 使用甲基化和沉默的 GFP 报告基因选择系统来识别关键导致肿瘤细胞表观遗传重新激活的途径和药物组合。这该项目将提供 AML 预后的新标志物以及基于将表观遗传调节纳入该疾病的护理标准。摘要：DNA 甲基化是附着在 DNA 上的标签，通过阻止 RNA 来改变基因功能形成。地西他滨是一种改变 DNA 甲基化的药物，可用于治疗白血病。我们建议核实 DNA 甲基化可以识别可以通过化疗治愈的患者。我们还建议使用地西他滨可预防 AML 复发，我们将找到增强地西他滨活性的药物，并且可以被引入临床试验