CommentaryHDAC inhibitors: Clinical update and mechanism-based potential
Section snippets
Histone deacetylase inhibitors
The role of gene regulation by physical alterations of either DNA or the structural components of chromatin has recently been highlighted as a major process in neoplastic transformation and maintenance of the malignant phenotype. The discovery that chromatin contains a dynamic group of nuclear proteins that regulate transcription of many genes and especially some tumor suppressor genes came about with the discovery that the histone deacetylases (HDACs) were the target for a potent natural
HDAC inhibitors in clinical development
HDACIs currently in clinical development cover pan-HDACIs (vorinostat, belinostat, and LBH589) and somewhat isotype selective agents (romidepsin, MS-275 and MGCD0103) (Table 2, Table 3). With the approval of Zolinza (vorinostat, SAHA) by the FDA for the treatment of CTCL and with other histone deacetylase inhibitors awaiting approval for various cancers, this will hopefully prompt the investigation of histone deacetylase inhibitors into a broader range of disease states where altered chromatin
Mechanism-based potential of HDACIs: are HDACIs being utilized in combinations that make mechanistic sense to achieve optimal therapeutic potential?
Several factors enter into paradigms of therapeutic combinations with epigenetic modulators: first, and the first demonstrated utility of HDACIs [54], the presence of oncogenic fusion proteins that incorporate HDACs or make high affinity complexes with HDACs; second, what are the genes regulated by these agents and how are they regulated; third, are these direct effects on proteins involved in apoptosis or client protein stability; fourth, are these effects due to direct induction of oxidative
Summary
With the approval of vorinostat for the treatment of CTCL and PTCL, the application of epigenetic regulation as an avenue in treatment has expanded, not only for hematological malignancies, but also to a much broader range of cancers. The response rates in CTCL are impressive and the side effects are manageable. The greatest utility of these epigenetic modulators will be in combination with other therapeutics that synergize with the regulation being controlled by the epigenetic modulator. Only
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