Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas

Abstract

Reversible acetylation is mediated by histone deacetylase (HDAC), which is involved in regulating a broad repertoire of physiological processes, many of which are under aberrant control in tumor cells. Inhibition of HDAC activity prompts tumor cells to enter apoptosis; therefore, the utility of HDAC inhibitors for the treatment of cancer has been investigated and several HDAC inhibitors have now entered clinical trials. Although the clinical picture is evolving and the precise clinical utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumor types have a favorable response to such agents. Hematological malignancies seem to be particularly sensitive, and vorinostat (also called suberoylanilide hydroxamic acid) has recently been approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. There are considerable gaps in our understanding of how HDAC inhibitors exert their antitumor activity. In the absence of mechanistic insights into the apoptotic process or biomarkers that inform on responsive tumors, it is a challenge to predict tumor response to HDAC-inhibitor-based therapies with any degree of certainty. In this Review, we discuss recent developments in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and relate this information to the emerging clinical picture for the treatment of cutaneous T-cell lymphoma and related malignancies.

Key Points

  • Reversible acetylation of histones on chromatin is an important level of epigenetic control, and it is becoming increasingly clear that acetylation affects many of the key processes that drive tumorigenesis, including the cell cycle, apoptosis, angiogenesis and invasion

  • Histone deacetylases (HDACs) are a family of related enzymes that regulate the level of lysine acetylation on substrate proteins, which is frequently aberrant in tumor cells, whereas histone acetyl transferases add acetyl groups to lysine residues

  • Small-molecule inhibitors of HDAC cause tumor cells to enter apoptosis; however, it is not known with any degree of certainty how inhibition of HDAC activity causes tumor-cell death, although several mechanisms have been proposed

  • At the moment, only one HDAC inhibitor, vorinostat, has been approved by the FDA for the treatment cutaneous T-cell lymphoma, on the basis of a phase II study in patients with progressive disease following two systemic therapies

  • Although the clinical efficacy of HDAC inhibitors for cutaneous T-cell lymphoma has been demonstrated in phase II proof-of-concept clinical trials, this utility has not been identified for other tumors; consequently, there is a need to identify biomarkers that determine tumors likely to have a favorable clinical response

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Figure 1: Structure of representative compounds from the major classes of histone deacetylase inhibitors.
Figure 2: The multiple roles of histone deacetylase (HDAC) in cells.
Figure 3: Schematic representation of the mechanism by which malignant T-cells home to the skin and the subsequent inflammatory response in CTCL.

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Acknowledgements

We thank Rosemary Williams for help in preparing the manuscript. Research in our laboratory is supported by Cancer Research UK, the Medical Research Council, the Association for International Cancer Research, the Leukaemia Research Fund and the European Union.

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Correspondence to Nicholas B La Thangue.

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Khan, O., La Thangue, N. Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas. Nat Rev Clin Oncol 5, 714–726 (2008). https://doi.org/10.1038/ncponc1238

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