HDAC Inhibitors in Cancer Care
The epigenetic control of gene expression has been shown to play an important role in cancer initiation, progression, and resistance. Thus, agents that modify the epigenetic environment of tumors will likely be an important addition to the anticancer arsenal. Specifically, there is much interest in modulating histone acetylation using a new class of drugs, histone deacetylase (HDAC) inhibitors. Preclinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging preclinical data, numerous HDAC inhibitors are being investigated in clinical trials either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy, or radiation therapy. In fact, vorinostat and depsipeptide, two actively studied HDAC inhibitors, were recently approved for the treatment of refractory cutaneous T-cell lymphoma. Although the use of HDAC inhibitors has generated great enthusiasm, a significant amount of work still needs to be done in order to understand their mechanisms of action, as well as to determine the appropriate patient characteristics and subsets of cancer for which HDAC inhibitors hold the most potential for effective treatment.
The epigenetic control of gene expression has been shown to play an important role in cancer initiation, progression, and resistance. Thus, agents that modify the epigenetic environment of tumors will likely be an important addition to the anticancer arsenal. Specifically, there is much interest in modulating histone acetylation using a new class of drugs, histone deacetylase (HDAC) inhibitors. Preclinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging preclinical data, numerous HDAC inhibitors are being investigated in clinical trials either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy, or radiation therapy. In fact, vorinostat and depsipeptide, two actively studied HDAC inhibitors, were recently approved for the treatment of refractory cutaneous T-cell lymphoma. Although the use of HDAC inhibitors has generated great enthusiasm, a significant amount of work still needs to be done in order to understand their mechanisms of action, as well as to determine the appropriate patient characteristics and subsets of cancer for which HDAC inhibitors hold the most potential for effective treatment.
The term epigenetics refers to changes in genetic expression and cellular phenotype without alterations in the DNA sequence itself. Alterations in the cellular epigenetic environment, and not only primary genetic mutations, play an important role in tumor formation, progression, and resistance to treatment. One of the critical epigenetic events in oncology is related to aberrant histone modifications.[1] In normal cellular biology, histones play a key role in regulating chromatin structure and function. Post-translational modifications of histone proteins through acetylation, methylation, and phosphorylation determine how these histone proteins control chromatin remodeling.
More specifically, histone acetylation is regulated through the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), where HATs transfer acetyl moieties to lysine residues and HDACs remove these acetyl moieties. HAT activity relaxes chromatin, permitting various transcription factors to interact with DNA, thereby promoting transcription. In contrast, HDAC activity condenses chromatin, preventing access of transcription factors, leading to transcriptional repression.[2] HAT inactivity and HDAC overactivity have been associated with tumorigenesis.[3] Due to the fact that it is pharmacologically much simpler to inhibit an enzyme rather than to induce one, HDAC inhibition has gained enormous clinical interest as an anticancer strategy.
However, it is not only the histone targets that enable HAT and HDAC disturbances to lead to tumor development. HAT/HDACs are also able to acetylate or deacetylate numerous other nonhistone targets, such as proteins involved in cellular proliferation, migration, cell death, DNA repair, angiogenesis, inflammation, and the immune response,[4] all of which play roles in tumor formation and progression. Correspondingly, HDAC inhibitors have been shown to be effective therapeutic anticancer agents via multiple mechanisms, including inducing cell-cycle arrest, intrinsic and extrinsic apoptotic mechanisms, mitotic cell death, autophagic cell death, reactive oxygen species, inhibiting angiogenesis,[4] and improving NK cell–mediated tumor immunity.[5] These diverse effects on cancer cells make HDAC inhibitors attractive agents not only for monotherapy but also for combination therapy with other anticancer modalities. Although many combination strategies have been shown to be both effective and synergistic, the exact mechanism(s) for this synergy are poorly understood and likely different according to the combination regimen utilized.
TABLE 1
Examples of the Many Currently Active Clinical Trials Involving HDAC Inhibitors