The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

“…Epigenetic mechanisms are well known to play a key role in fibrosis (Helling and Yang, 2015;Page and Mann, 2015;Yang and Schwartz, 2015). Specifically in pulmonary fibrosis and fibroblast biology, changes in DNA methylation (Huang et al, 2014;Qu et al, 2018;Sanders et al, 2012;Yang et al, 2014), microRNAs (Khalil et al, 2015;Liu et al, 2010;Miao et al, 2018;Yang et al, 2013) and histone-modifying enzymes (Bai et al, 2019;Bombardo et al, 2018;Conforti et al, 2017;Coward et al, 2014Coward et al, , 2009Glenisson et al, 2007;Hemmatazad et al, 2009;Khalil et al, 2015;Korfei et al, 2015;Ota et al, 2015;Sanders et al, 2014Sanders et al, , 2017 have been shown to accompany and drive lung fibroblast activation and disease progression. Our screen interrogated the effects of a multitude of epigenetic-modifying small molecules, and identified effects of a variety of epigenetic writers, erasers and readers, demonstrating the complexity and importance of epigenetic regulators in controlling fibroblast biology.…”

“…BRD4) (Tang et al, 2013) and EZH2 (Coward et al, 2018;Xiao et al, 2016) were identified. We chose to focus on pracinostat because it was most effective in our primary assay outcome, and because HDAC inhibition has proven effective in fibrosis models (Barter et al, 2010;Bombardo et al, 2018;Conforti et al, 2017;Glenisson et al, 2007;Guo et al, 2009;Kang et al, 2017;Khalil et al, 2015;Kim et al, 2018;Ota et al, 2015) but its anti-fibrotic effects remain poorly understood. However, we also note that inhibitors of several enzymes not previously linked to fibrosis were identified in our screen, such as L3MBTL3, a reader of methylated-lysine on histones (Min et al, 2007;Trojer et al, 2007).…”

“…HDACs primarily function by catalyzing the de-acetylation of histones resulting in gene repression; thus, inhibition of HDACs should result in an increase in transcriptional activity. Interestingly, while there is widespread evidence that HDAC inhibitors are effective in both in vitro and in vivo fibrosis models (Barter et al, 2010;Bombardo et al, 2018;Conforti et al, 2017;Glenisson et al, 2007;Guo et al, 2009;Kang et al, 2017;Khalil et al, 2015;Kim et al, 2018), there is a lack of understanding of how HDAC inhibition reduces fibroblast activation and fibrosis. Moreover, while several HDAC inhibitors were highly effective at reducing αSMA in our screen, others were less so (entinostat and tacedinaline), while still others actually enhanced the level of αSMA (CS-055, RSC133 and TC-H 106), highlighting the fact that specific HDACs and HDAC inhibitors likely act via distinct targets and mechanisms to regulate fibroblast biology.…”

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

“…HDAC inhibitors have been studied extensively in the treatment of malignancy, and some have gained approval as antitumor therapies (18). Recently, several studies have also demonstrated that HDAC inhibitors are effective in attenuating the development and progression of fibrosis in several organs, including kidney, heart, and lung (19)(20)(21)(22). Most of those observations, however, are based on the use of pan-HDAC inhibitors.…”

Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

“…In addition, other studies revealed the important synergistic roles of cellular contractility (via relaxin) and tissue stiffness (via LOXL2) in the maintenance of fibrosis suggesting that these two inter-related mechanisms should be targeted concomitantly 28 . Finally, LOX is emerging as a potentially useful companion biomarker for evaluation of early on-target effects of other anti-fibrotic agents29 . Our translational studies using both normal and IPF cells highlight that targeting the cross-linking of collagen alters properties of primary lung fibroblasts that at least in vitro appeared to enhance the functional and synthetic properties of these cells.These findings coupled with the lack of efficacy of Simtuzumab in a humanized SCID mouse model of pulmonary fibrosis highlight the need to further exploration of an IPF target beyond that of a bleomycin-induced pulmonary fibrosis model before proceeding to the clinic.…”