Amid a growing understanding about the role of epigenetics as a driver of cancer, researchers have turned their attention to a key player in the process: histone deacetylases (HDACs).
HDACs are enzymes responsible for acetylation, which essentially functions to repress gene transcription, and targeting this activity through small-molecule inhibitors has proved effective in hematologic malignancies.
In February 2015, the FDA approved panobinostat (Farydak) in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma. That decision marked the fourth HDAC inhibitor that the regulatory agency has approved during the past decade.
Despite these demonstrable clinical successes in hematologic malignancies, HDAC inhibitors have proved impotent in the treatment of solid tumors, which has limited their utility. That may be changing, however, with a better understanding of the role of histone acetylation in the context of global epigenetic and genetic modifications in cancer.
More recently, researchers are seeing the first hints of clinical efficacy in solid tumors with next-generation, class-specific, and multitargeted HDAC inhibitors. Multiple agents are advancing in clinical development (Table)
The Epigenetics of Cancer
The classical view of cancer is as a genetic disease, driven by changes such as mutations to the sequence of genes involved in hallmark cellular processes such as growth and proliferation. In the past several decades, it has become clear that epigenetic abnormalities that alter gene expression without changing the DNA sequence are equally important. Epigenetics describes a secondary layer of regulation of the genetic material; while the specific sequence of DNA in a gene instructs the cell about what to make, epigenetics dictates when and where it will be made.
In cells that are not dividing, the genetic material is packaged up in the form of chromatin, composed of negatively charged DNA wound tightly around positively charged histone proteins like thread on a spool. Both thread (DNA) and spool (histones) can be modified by the addition and removal of chemical groups, mediated by groups of opposing enzymes.
At least 8 distinct types of modification have been described, including acetylation, methylation, phosphorylation, and ubiquitination. The specific pattern of modifications, attained by a balance between the different enzymes that govern them, acts as a kind of regulatory code for the genetic material, ultimately dictating gene expression. Disruption of this delicate balance has been associated with the development of a wide variety of human cancers.
Nuances of Targeting HDACs
Acetylation and deacetylation, the addition and removal of acetyl groups, is governed by enzymes known as histone acetylases (HATs) and histone deacetylases (HDACs), respectively. Acetylation is among the best-characterized modifications of the histone proteins.
Although it is increasingly appreciated that the role of histone acetylation is vastly more complex than originally thought and likely acts in concert with other epigenetic modifications, researchers believe that acetylation changes the confirmation of the histone “spool,” loosening it and rendering the DNA more accessible and, in turn, more transcriptionally active.
HDAC Inhibitors in Action
This illustration captures the diverse proteins and processes that potentially could be affected by inhibiting HDAC enzymes.
HDAC indicates histone deacetylase; HR, homologous recombination; NHEJ, non-homologous end joining; ROS, reactive oxygen species.
Mottamal M, Zheng S, Huang TL, Wang G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules. 2015;20:3898-3941. doi:10.3390/molecules20033898.
The fact that epigenetic regulation plays such a key role in gene expression and that it may form part of the genomic manipulations of cancer cells has fueled significant interest in drugging the epigenetic enzymes, since these are readily targeted with small molecule drugs.
HDACs are a large family of 18 enzymes that are divided into 4 classes based on how similar they are to yeast HDACs, where they are found in the cell, and their function. Classes I, II, and IV are considered the classical HDACs, consisting of 11 zinc-dependent metalloproteins and have been the key focus of drug development efforts. The class III HDACs are known as sirtuins, and the 7 enzymes in this group are nicotinamide adenine dinucleotide (NAD+)-dependent proteins. This group is unaffected by currently available HDAC inhibitors; however, efforts to develop sirtuin-targeting agents are under way, although these studies are predominantly in the preclinical stages.