Department of Oncology, Hammersmith Hospital Campus, Imperial College London, UK.
Future Med Chem. 2009 Nov;1(8):1481-95. doi: 10.4155/fmc.09.105.
The term epigenetic landscape was coined by CH Waddington to describe how cell fates were established in development, visualized as valleys and ridges directing the irreversibility of cell type differentiation. It is now clear that normal differentiation control breaks down during tumor development and that all tumor types show aberrant regulation of the epigenetic code, including changes in DNA methylation, histone modification and microRNAs. This has led to much interest in the development of epigenetic cancer therapies to target this aberrant epigenetic regulation. Histone deacetylase and DNA methyltransferase inhibitors are now used in the treatment of certain hematological malignancies. However, their more general applicability to solid tumors may be limited by lack of specificity and delivery challenges. Approaches to overcome these limitations and how to develop more specific drugs are discussed. The use of RNAi in the context of genome regulation as well as the possibility to use polyamides and engineered zinc fingers to target master regulators in the future is examined. Ultimately, improved specificity of epigenetic therapies will require increased mapping of the aberrant epigenetic landscape in cancer and cancer-specific target validation using chemical epigenetic approaches.
“表观遗传学景观”这一术语由 CH Waddington 创造，用于描述细胞命运在发育过程中是如何建立的，其可视化形式为指导细胞类型分化不可逆性的山谷和山脊。现在很清楚的是，正常分化控制在肿瘤发展过程中会崩溃，所有肿瘤类型都表现出表观遗传密码的异常调节，包括 DNA 甲基化、组蛋白修饰和 microRNAs 的变化。这导致了人们对开发针对这种异常表观遗传调节的表观遗传癌症疗法产生了浓厚的兴趣。组蛋白去乙酰化酶和 DNA 甲基转移酶抑制剂现在用于治疗某些血液系统恶性肿瘤。然而，由于缺乏特异性和传递挑战，它们更广泛地应用于实体瘤可能受到限制。本文讨论了克服这些限制的方法以及如何开发更具特异性的药物。还研究了在基因组调控背景下使用 RNAi 的可能性，以及未来使用多聚酰胺和工程化锌指靶向主调控因子的可能性。最终，表观遗传学疗法的特异性提高将需要增加对癌症中异常表观遗传学景观的映射，并使用化学表观遗传学方法对癌症特异性靶标进行验证。
