Aberrant epigenetic regulation: a central contributor to lung carcinogenesis and a new therapeutic target.
Aberrant epigenetic regulation: a central contributor to lung carcinogenesis and a new therapeutic target.
复制标题
DOI：
10.1200/edbook_am.2013.33.e295
复制
发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Rudin, Charles M
中科院分区：
文献类型：
--
作者：
Juergens, Rosalyn A;Rudin, Charles M
致癌是由遗传和表观遗传异常共同驱动的。在肺癌和其他实体肿瘤中，基因启动子甲基化模式和组蛋白乙酰化的异常与肿瘤抑制基因的沉默有关。关键表观遗传修饰的鉴定已被证明是早期非小细胞肺癌的预后。先前的临床试验旨在用单药去甲基化剂或组蛋白去乙酰化酶抑制剂在最大耐受剂量下修饰表观基因组，结果令人失望。最近的一项临床试验显示，同时使用“表观遗传靶向”剂量的去甲基化剂和组蛋白去乙酰化酶抑制剂的组合取得了令人鼓舞的结果，包括一名患者有完全的客观反应。与该临床试验相关的生物标志物表明，在治疗一个月后，在外周血中检测到强烈的去甲基化的患者，确定了那些从这种新的治疗策略中获益最多的患者。根据观察，在给予联合表观遗传治疗后，对后续治疗的反应异常持久，表观遗传治疗也可能在“启动”患者对标准细胞毒性治疗或免疫治疗有更好的反应方面发挥作用。本文将回顾过去40年来表观遗传学在肺癌中的作用以及表观遗传学治疗肺癌的历史。
Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at "epigenetically targeted" doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in "priming" patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.