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首页> 外文期刊>Expert opinion on therapeutic targets >DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors
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DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

机译：DNMTs作为高危儿科胚胎脑肿瘤的潜在治疗靶标

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Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.
机译：恶性脑瘤是儿童与癌症相关的发病率和死亡率的主要原因，它跨越具有不同临床表型的多种疾病，但可能具有非常相似的形态特征。直到最近，很少发现儿童脑肿瘤的分子标记物，这限制了治疗进展。最近的全球基因组学研究已使儿童脑肿瘤的分子分类功能强大，并鉴定和巩固了罕见的，看似完全不同的临床实体。现在越来越明显的是，表观遗传过程的失调实质上促进了肿瘤表型的异质性，并且包括癌症起始和进展的重要驱动力。具体而言，DNA高甲基化和通过DNA甲基转移酶（DNMT）沉默关键的肿瘤抑制基因已成为脑肿瘤发病机制中的重要和基本机制。最近在侵略性小儿胚胎性脑肿瘤中发现了TTYH1-C19MC基因融合体，这些发现突出了这些发现，这导致C19MC相关脑肿瘤中神经特异性DNMT3B亚型的失调和表达增加。我们的观察结果表明，DNMT和组蛋白脱乙酰基酶的药理学抑制剂可显着抑制源自C19MC相关肿瘤的细胞的生长，这表明靶向表观基因组修饰剂是针对这些高度耐药的肿瘤的新型治疗方法。

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