An overview of investigational Histone deacetylase inhibitors (HDACis) for the treatment of non-Hodgkin’s lymphoma

ABSTRACT

Introduction: Histone acetylation alters DNA transcription and protein expression. Aberrant acetylation is seen in tumor cells. Histone deacetylase inhibitors (HDACis) act by modifying gene expression and are the newest class of drugs shown to be promising in patients with several malignancies including relapsed and/or refractory lymphoma. Multiple HDACis are currently under various phases of clinical trials for the treatment of Non-Hodgkin’s lymphoma (NHL).

Areas Covered: This review discusses the mechanism of histone acetyl transferases (HAT’s), histone deacetylases (HDAC’s) and their role in B - and T-cell malignancies with a particular focus on the mechanism of action and clinical application of HDACis in NHL. Discussion includes: HDACi’s like vorinostat, romidepsin, belinostat, panobinostat, entinostat and chidamide; pivotal clinical trials leading to the approval of HDACis in NHL; ongoing active clinical trials and combination therapies with novel agents.

Expert opinion: Relapsed and or refractory lymphoma poses a challenge to the clinician given the poor outcomes.

HDACis show promising clinical activity in patients with relapsed/refractory NHL. Active pursuit of developing newer HDACis and clinical trials using combination therapies that help understand the molecular characteristics and synergistic actions of these agents is warranted. This would help improve efficacy, drug tolerability and expand the horizon of these novel agents.

KEYWORDS:

• Histone deacetylase inhibitors
• non-hodgkin’s lymphoma
• mechanism of action
• and clinical trials

Article highlights

• HATs and HDACs regulate gene transcription by altering acetylation of histones and nonhistone substrates.

• In B-cell and T-cell malignancies, reduction in histone and TF acetylation correlates with proliferation and survival whereas increased acetylation causes tumor growth arrest and cell death.

• HDACis can induce tumor cell apoptosis, growth arrest, differentiation, immunogenicity, and inhibit angiogenesis by blocking the activity of HDAC enzymes.

• Vorinostat was the first HDACi approved for the treatment of NHL. This drug caused hyperacetylation of histones, leading to changes in gene expression involved in cell-cycle regulation and MAPK signaling.

• Romidepsin plays a key role in pathways involving chaperone proteins Hsp90, Hsp70, and TFs C-MYC and p53 in addition to HDAC inhibition.

• Belinostat may be considered for the treatment of NHL in patients with thrombocytopenia with platelet counts less than 100,000.

• Valproic acid, vorinostat, and entinostat exhibited synergy in preclinical models when combined with rituximab.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Angela Reagan of the Moffitt Cancer center for her editorial assistance.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.