Mummaneni Padmaja, Shord Stacy S
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland.
Pharmacotherapy. 2014 May;34(5):495-505. doi: 10.1002/phar.1408. Epub 2014 Mar 11.
Epigenetic modifications play a critical role in the development of pediatric and adult cancers, contributing to the cumulative changes observed as normal cells undergo malignant transformation. These modifications have been studied to develop epigenome-targeted therapies and new diagnostic tools. The U.S. Food and Drug Administration has approved four epigenome-targeted anticancer drugs. Two are drugs that inhibit DNA methyltransferases: azacitidine and decitabine, and two are drugs that inhibit histone deacetylases: vorinostat and romidepsin. These initial successes demonstrate the potential effectiveness of epigenome-targeted therapies as monotherapy in hematologic malignancies, but newer studies are focused on combination therapy in many cancers. Epigenetic modifications have also been used to evaluate potential biomarkers to diagnose patients with cancer, identify patient populations likely to respond to specific anticancer therapies, and select reasonable dosages for investigational anticancer drugs, as observed with other newer targeted anticancer drugs. Although much has been learned about the relationship between the epigenome and cancer, many questions remain unanswered at this time. The next step is to continue to translate emerging epigenetic knowledge into anticancer drug development. In this review, we discuss the role of epigenetic modifications in the development of cancer and anticancer drug resistance, and we describe the progress and challenges associated with developing epigenome-targeted anticancer drugs and diagnostic tools that identify epigenetic modifications.
表观遗传修饰在儿童和成人癌症的发展中起着关键作用，促使正常细胞发生恶性转化时出现累积性变化。人们对这些修饰进行了研究，以开发针对表观基因组的疗法和新的诊断工具。美国食品药品监督管理局已批准了四种针对表观基因组的抗癌药物。两种是抑制DNA甲基转移酶的药物：阿扎胞苷和地西他滨，另外两种是抑制组蛋白脱乙酰酶的药物：伏立诺他和罗米地辛。这些初步成功证明了针对表观基因组的疗法作为血液系统恶性肿瘤单一疗法的潜在有效性，但最新研究聚焦于多种癌症的联合治疗。与其他新型靶向抗癌药物一样，表观遗传修饰也已用于评估潜在生物标志物，以诊断癌症患者、识别可能对特定抗癌疗法有反应的患者群体，并为研究性抗癌药物选择合理剂量。尽管人们对表观基因组与癌症之间的关系已有很多了解，但目前仍有许多问题未得到解答。下一步是继续将新出现的表观遗传知识转化为抗癌药物研发。在本综述中，我们讨论了表观遗传修饰在癌症发展和抗癌药物耐药性中的作用，并描述了在开发针对表观基因组的抗癌药物和识别表观遗传修饰的诊断工具方面的进展与挑战。
