Cancer epigenetics drug discovery and development: the challenge of hitting the mark

Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved “first generation” of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin). This Review provides an analysis of prospects for discovery and development of novel cancer agents that target epigenetic proteins. We will examine key examples of epigenetic dysregulation in tumors as well as challenges to epigenetic drug discovery with emerging biology and novel classes of drug targets. We will also highlight recent successes in cancer epigenetics drug discovery and consider important factors for clinical success in this burgeoning area. Epigenetic dysregulation in cancer Epigenetic information is contained in the cell in multiple forms that include DNA methylation, histone modification (methylation, acetylation, phosphorylation, etc.), nucleosome positioning, and microRNA expression, among others. This combined information constitutes the epigenome. A comprehensive understanding of epigenomic dysregulation in specific cancer types has not been elucidated yet. Currently, there is an understanding of tumor-specific types of epigenetic modifications without a full appreciation of the context of the entire cancer epigenome in the specific tumor. Cancer epigenetic dysregulation can be categorized into three types: (a) altered DNA or histone modification, (b) somatic alteration in an epigenetic protein, and (c) altered expression of an epigenetic protein. Those types of cancer epigenome dysregulation have been reviewed comprehensively elsewhere (1–3), and only will be referred to here.