Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Curr Neuropharmacol. 2023;21(7):1519-1535. doi: 10.2174/1570159X20666220922150456.
Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal progress in patients' prognosis. Emerging molecular targets and mechanisms have revealed novel approaches for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetic research and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination of chemoand immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could possibly be used against the most common malignant tumors of childhood, such as medulloblastomas, high-grade gliomas and ependymomas.
儿科脑恶性肿瘤是儿童癌症相关死亡的最常见原因。手术、放疗和化疗的治疗方案改善了患者的管理，但患者的预后几乎没有改善。新兴的分子靶点和机制为儿科脑肿瘤治疗提供了新的方法，实现了个性化医疗。表观遗传学研究的进展及其与遗传变化的相互作用丰富了我们对这些肿瘤分子异质性的认识，并揭示了影响肿瘤进展关键信号通路的重要基因。表观遗传学治疗的巨大潜力主要在于表观遗传改变的广泛位置和可逆性，提出了广泛的靶向选择，包括化学疗法和免疫疗法的可能联合，显著提高了它们的疗效。表观遗传学药物，包括 DNA 甲基转移酶、组蛋白去乙酰化酶和去甲基酶抑制剂，目前正在儿科脑肿瘤的临床试验中进行测试。其他新型表观遗传学药物包括调节表观遗传修饰途径的蛋白质和酶抑制剂，如 Bromodomain 和 Extraterminal (BET) 蛋白、Cyclin-Dependent Kinase 9 (CDK9)、AXL、Facilitates Chromatin Transcription (FACT)、BMI1 和 CREB Binding Protein (CBP) 抑制剂，可单独使用或与当前治疗方法联合使用。在这篇综述中，我们讨论了针对儿童最常见恶性肿瘤（如髓母细胞瘤、高级别胶质瘤和室管膜瘤）的表观遗传学药物的最新进展。
