Mechanism of combined 'epigenetic therapy' in myeloid malignancies

描述（由申请人提供）：组蛋白去乙酰化酶（HDAC）抑制剂（HDACi）和DNA甲基转移酶（DNMT）抑制剂（DNMTi）联合使用可能会在髓系恶性肿瘤患者中诱导比单独使用DNMTi更深刻的临床反应。然而，临床反应与这些药物组合在体外通过逆转启动子甲基化逆转甲基化基因转录沉默的能力之间的关系仍然不确定。除了对表观遗传转录控制的影响外，这两类药物都可能导致DNA损伤。E1905是一项随机II期组间试验，在髓系恶性肿瘤患者中进行，旨在评估对DNMTi 5-阿扎胞苷（SAC）新方案的临床反应率，单独使用或与口服HDACi MS-275联合使用，以确定与单独使用DNMT抑制剂相比，添加HDACi是否增加了临床反应的数量或完全和部分反应的百分比。本申请中提出的相关研究将确定对DNMTi单独或与HDACi联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研究与MDS和AML特异性相关的特定甲基化启动子，以确定基因甲基化逆转和这些基因重新表达与SAC + MS-275临床反应相关的频率。一项基于基因组学的甲基化和甲基化变化的互补研究将用于鉴定候选基因和基因群，其甲基化模式或甲基化逆转可能与治疗反应特异性相关并预测治疗反应。我们还将探讨这些药物的临床效果源于其DNA损伤特性的另一种假设：确定SAC + MS-275诱导双链DNA断裂的频率，并定义这种DNA损伤与临床反应诱导之间的关系。了解这些药物在髓系恶性肿瘤中临床活性的潜在机制，将极大地促进进一步的药物开发和临床试验设计，因为表观遗传学科学被转化为其他癌症的治疗。

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.