Approaches to target the genome and its epigenome in cancer

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.