The emergence of specific HDAC inhibitors and their clinical efficacy in the treatment of hematologic malignancies and breast cancer

Abstract

The dynamic balance between histone acetylation and deacetylation is an important epigenetic mechanism controlling gene expression, and is associated with the etiology and progression of many human diseases. Early success of histone deacetylase (HDAC) inhibition in the treatment of hematological cancers paved the way for the development and testing of many different pan/global histone deacetylase inhibitors (HDIs). Dose limiting toxicities in these early trials, coupled with increased understanding of the differential expression patterns of HDACs in different tissues and disease states, led to the emergence of more specific HDIs that target specific HDAC classes and isotypes. Whereas a large number of clinical trials have been undertaken using pan-HDIs, which have demonstrated varying success in the treatment of hematological and solid malignancies, both as single agents and in combination with other drugs, there have been far fewer undertaken with the emerging repertoire of specific HDIs, which could potentially overcome the limitations seen in the pan inhibitors. In this review we describe the classification and development of HDIs as well the roles of HDACs in cancers, and the rationale behind moving toward more selective inhibition. We then examine the clinical efficacy of both pan- and specific HDI treatment by reviewing a number of clinical trials, focusing on hematological malignancies, where numerous trials have demonstrated single agent and combinatory efficacy, as well as breast cancers, where fewer trials have been undertaken showing limited efficacy, but also where promising pre-clinical findings necessitate further clinical investigation.