Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes

ABSTRACT

Introduction: Epigenetic changes and mutations in epigenetic modifiers characterize and likely drive many cases of acute myeloid leukemia and myelodysplastic syndrome. Development of DNA methyltransferase inhibitors has been most successful in these diseases. While many epigenetic marks are potential targets of cancer therapies, histone deacetylase inhibitors (HDACi) have undergone the most advanced development to date.

Area Covered: In this review, the authors describe and discuss the biology and the clinical results of HDAC inhibitors in the settings of myeloid malignancies.

Expert opinion: While significant results have been achieved in lymphoma and myeloma, efficacy remains limited in myeloid malignancies for both single agent and HDACi based combination regimens. The redundancy and the pleiotropic activity of HDACi (on both histone and non-histone proteins) are key factors that have limited to date the selection of patients and the design of robust biomarkers. Recent advances in biology (mechanisms of resistance, immunology) and the design of a more specific third generation of HDACi are two important features that will drive the future clinical development of HDACi in myeloid malignancies.

KEYWORDS:

• Histone deacetylase inhibitors
• HDACi
• myeloid malignancies
• AML
• MDS
• HDACi based combination therapy
• Epigenetics
• Vorinostat
• Immunotherapy
• Hypomethylating agents

Article highlights

• Epigenetic dysregulation is a common feature in myeloid malignancies. HDACs are critical regulators of gene expression that enzymatically remove the acetyl group from histones.

• HDACi have multiple different mechanisms of action besides histone modification, including both transcriptional effects and non-transcriptional effects. They have pleiotropic actions that partially depend on the cell (differentiation, growth arrest, apoptosis, senescence, immunogenicity, or inhibition of angiogenesis).

• In myeloid malignancies, promising data from in vitro studies did not translate yet into significant clinical benefit.

• Identification of the driving mechanism of action in specific cell types, development of biomarkers, and a refined evaluation of combination approaches (for both pharmacodynamic and toxicity issues) are the three main challenges in HDACi development.

• Promising future directions are the development of isotype-specific HDACi (HDAC3 and HDAC6) as well as combination of HDACi with chemotherapy, other epigenetic therapies, and/or next-generation immunotherapies.

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Financial and Competing Interests Disclosure

T Prebet and N Vey have received research support from Merck Sharp and Doehme and honoraria from Novartis. S Gore has received research support from Syndax and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.