Chapter 17 - Present and future perspectives for targeting histone modifications in therapy

Abstract

The contribution of epigenetic alterations in tumor development and progression is firmly established. The epigenetic code comprises both DNA and histone modifications that must be flexible enough to adapt and respond to developmental and environmental cues in an appropriate way. This plasticity is essential for correct gene expression in a cell-type-specific and time-precise manner. The epigenetic status of a given cell is the net result of the action of multiple enzymes that add, interpret, or remove specific epigenetic marks. The frequent deregulation of epigenetic proteins’ expression and function in many diseases, including cancer, makes them predictable therapeutic targets. As the number of inhibitors targeting these epigenetic proteins grows, much effort is being put into improving isoform selectivity and decreasing systemic toxicity without compromising potency. However, so far, only five HDAC inhibitors have been approved as a second or third line of treatment for three distinct hematological malignancies. Unfortunately, their efficacy on solid tumors remains disappointing. Nevertheless, as our understanding of the biological processes underlying diseases increases, so does the opportunity for drug combinations. We anticipate that clinical trials aiming to explore the combination of epigenetic modulators with targeted therapies and immunomodulatory drugs will improve patients’ care in the short/median term.