Elsevier

Biochemical Pharmacology

Volume 74, Issue 5, 1 September 2007, Pages 659-671
Biochemical Pharmacology

Commentary
HDAC inhibitors: Clinical update and mechanism-based potential

https://doi.org/10.1016/j.bcp.2007.04.007Get rights and content

Abstract

Recently, the role of transcriptional repression through epigenetic modulation in carcinogenesis has been clinically validated with several inhibitors of histone deacetylases and DNA methyltransferases. It has long been recognized that epigenetic alterations of tumor suppressor genes was one of the contributing factors in carcinogenesis. Inhibitors of histone deacetylase (HDAC) de-repress genes that subsequently result in growth inhibition, differentiation and apoptosis of cancer cells. Vorinostat (SAHA), romidepsin (depsipeptide, FK-228), belinostat (PXD101) and LAQ824/LBH589 have demonstrated therapeutic benefit as monotherapy in cutaneous T-cell lymphoma (CTCL) and have also demonstrated some therapeutic benefit in other malignancies. The approval of the HDAC inhibitor vorinostat (Zolinza™) was based on the inherent sensitivity of this type of lymphoma to alterations in acetylation patterns that resulted in the induction of repressed apoptotic pathways. However, the full potential of these inhibitors (epigenetic modulators) is still on the horizon, as the true breadth of their utility as anti-cancer agents will be determined by the careful analysis of gene expression changes generated by these inhibitors and then combined with conventional chemotherapy to synergistically improve response and toxicity for an overall enhanced therapeutic benefit to the patient. The question that must be considered is whether the current HDACIs are being utilized to their fullest potential in clinical trials based on their mechanism-based alterations in disease processes.

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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