The Sequential Combination Paradigm in Epigenetic Therapy

Abstract

Copyright: © 2012 Fandy TE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Epigenetic therapy is a novel therapeutic approach that targets DNA methylation, histone modifications or microRNAs (miRNAs). Drugs targeting DNA methylation (azacitidine and decitabine) and histone acetylation (vorinostat) are currently FDA-approved for the treatment of Myelo Dysplastic Syndromes (MDS) and cutaneous T-Cell Lymphoma (CTCL), respectively. Drugs targeting miRNAs and other histone modifications are currently in preclinical and clinical trials. A central hypothesis in epigenetic therapy is the combination of epigenetic modifiers in a specific sequential order to achieve optimal expression of epigenetically silenced tumor suppressor genes. This paradigm was established based on the observation that inhibitors of class I & II Histone Deacetylase (HDAC) enzymes cannot re-express genes silenced by promoter hypermethylation [1]. The use of a DNA Methyl Transferase (DNMT) inhibitor followed by an HDAC inhibitor is required for the re-expression of genes silenced by promoter hypermethylation. Consequently, the sequential or overlapping combination of DNA hypomethylating agents and HDAC inhibitors has been utilized in several clinical trials based on this hypothesis [2,3].