Mechanism of combined 'epigenetic therapy' in myeloid malignancies

骨髓恶性肿瘤联合“表观遗传学治疗”的机制

基本信息

批准号：
7676216
负责人：
STEVEN D GORE
金额：
$ 48.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676216
关键词：
Acute Myelocytic Leukemia Applications Grants Azacitidine Benzamides Binding Proteins Blood Cells Bone Marrow Candidate Disease Gene Chronic Myelomonocytic Leukemia Clinical Clinical Research Clinical Trials Design Complex Correlative Study CpG Islands CpG dinucleotide Cytogenetics Cytosine DNA Damage DNA Double Strand Break DNA Methylation DNA Methyltransferase DNA Methyltransferase Inhibitor DNA Modification Methylases Disease Dose Drug Combinations Dysmyelopoietic Syndromes Dysplasia Epigenetic Process Frequencies Gene Expression Gene Silencing Generations Genes Genomics Half-Life Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Hour In Vitro In complete remission Lead MS-275 Malignant Neoplasms Methylation Molecular Myeloproliferative disease Nucleosides Oral Patients Pattern Pharmaceutical Preparations Phase Phase I Clinical Trials Promoter Regions Property Randomized Randomized Controlled Clinical Trials Schedule Science Serum Sodium phenylbutyrate Therapeutic Transcriptional Regulation Translating base cancer cell clinical effect cohort design drug development drug mechanism gene repression genome-wide in vitro Model in vivo inhibitor/antagonist novel partial response promoter response treatment response

项目摘要

DESCRIPTION (provided by applicant): Combinations of histone deacetylase (HDAC) inhibitors (HDACi) and DNA methyltransferase (DNMT) inhibitors (DNMTi) may induce more profound clinical responses in patients with myeloid malignancies compared to DNMTi alone. However, the relationship between the clinical responses and the ability of these drug combinations to reverse transcriptional silencing of methylated genes in vitro through the reversal of promoter methylation remains uncertain. In addition to their effects on epigenetic transcriptional control, both classes of drugs can lead to DNA damage. E1905 is a randomized Phase II Intergroup trial in patients with myeloid malignancies designed to estimate clinical response rates to a novel schedule of the DNMTi 5- azacitidine (SAC), alone and in combination with the oral HDACi MS-275 to determine whether the addition of the HDACi increases the number of clinical responses or the percentage of complete and partial responses compared to the DNMT inhibitor alone. The correlative studies proposed in this application will determine whether clinical response to a DNMTi, alone or in combination with an HDACi, requires reversal of gene methylation and expression of epigenetically silenced genes. Specifically selected methylated promoters characteristically associated with MDS and AML will be studied using methylation-specific PCR to determine the frequency with which reversal of gene methylation and re-expression of these genes is associated with clinical response to SAC + MS-275. A complementary genomics-based study of methylation and methylation changes will be used to identify candidate genes and groups of genes whose methylation patterns or whose reversal of methylation may be specifically associated with and predictive of treatment response. The alternative hypothesis that the clinical effect of these drugs derives from their DNA damaging properties will also be explored: the frequency of induction of double stranded DNA breaks in response to SAC + MS-275 will be determined, and the relationship between such DNA damage and clinical response induction will be defined. Understanding of the mechanism underlying the clinical activity of these drugs in myeloid malignancies will greatly facilitate further drug development and clinical trial design as the science of epigenetics is translated to treatment for other cancers.

描述（由申请人提供）：与单独使用 DNMTi 相比，组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACi) 和 DNA 甲基转移酶 (DNMT) 抑制剂 (DNMTi) 的组合可能会在骨髓恶性肿瘤患者中诱导更深刻的临床反应。然而，临床反应与这些药物组合通过逆转启动子甲基化在体外逆转甲基化基因转录沉默的能力之间的关系仍不确定。除了对表观遗传转录控制的影响外，这两类药物还会导致 DNA 损伤。 E1905 是一项在骨髓恶性肿瘤患者中进行的一项随机 II 期组间试验，旨在评估单独使用 DNMTi 5-阿扎胞苷 (SAC) 以及与口服 HDACi MS-275 联合使用的新方案的临床反应率，以确定是否添加与单独使用 DNMT 抑制剂相比，HDACi 增加了临床反应的数量或完全反应和部分反应的百分比。本申请中提出的相关研究将确定对单独的 DNMTi 或与 HDACi 组合的临床反应是否需要逆转基因甲基化和表观遗传沉默基因的表达。将使用甲基化特异性 PCR 研究专门选择的与 MDS 和 AML 相关的甲基化启动子，以确定基因甲基化逆转和这些基因的重新表达与 SAC + MS-275 临床反应相关的频率。基于互补基因组学的甲基化和甲基化变化研究将用于识别候选基因和基因组，其甲基化模式或其甲基化逆转可能与治疗反应特别相关并可预测治疗反应。还将探讨这些药物的临床效果源自其 DNA 损伤特性的另一种假设：将确定响应 SAC + MS-275 诱导双链 DNA 断裂的频率，以及此类 DNA 损伤与将定义临床反应诱导。随着表观遗传学被转化为其他癌症的治疗，了解这些药物在骨髓恶性肿瘤中的临床活性机制将极大地促进进一步的药物开发和临床试验设计。