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Epigenetic targets in hematological malignancies: combination therapies with HDACis and demethylating agents

Chromatin modeling in DNA is fundamental to gene expression, DNA repair and replication. Methylation of promoter regions of tumor-suppressor genes and histone deacetylation leads to gene silencing and transcriptionally repressive chromatin. Histone deacetylase inhibitors and hypomethylating agents allow upregulation of proapoptotic genes and downregulation of antiapoptotic genes, and show significant single-agent anticancer activity, predominantly in cutaneous T-cell lymphoma and myelodysplasia, respectively. Combinations of these drugs are being employed in clinical trials to target multiple biological pathways, with the hope of synergistic pharmacodynamics. Preclinical studies of combinations of these agents with chemotherapy, monoclonal antibodies and small-molecule inhibitors are ongoing and demonstrate synergy in multiple hematological cancers, raising the prospect of future treatment for these diseases having a multitargeted approach.