Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease.

FIGURE 1

Schematic representation of the targets and effects of HDAC inhibitors (HDACi). In addition to directly regulating transcription through changes in chromatin structure, HDACi modulate the acetylation of transcription factors and other nonhistone proteins, leading to a range of biologic effects, including the promotion of apoptosis, cell cycle inhibition, immune modulation, and inhibition of angiogenesis.

FIGURE 2

Study design for phase III trial comparing vorinostat versus placebo in patients with previously treated malignant pleural mesothelioma (MPM).