Oncotarget

Research Papers:

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

Franco Conforti, Elizabeth R. Davies, Claire J. Calderwood, Thomas H. Thatcher, Mark G. Jones, David E. Smart, Sumeet Mahajan, Aiman Alzetani, Tom Havelock, Toby M. Maher, Philip L. Molyneaux, Andrew J. Thorley, Teresa D. Tetley, Jane A.­ Warner, Graham Packham, A. Ganesan, Paul J. Skipp, Benjamin J. Marshall, Luca Richeldi, Patricia J. Sime, Katherine M.A. O’Reilly, Donna E. Davies _

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Oncotarget. 2017; 8:48737-48754. https://doi.org/10.18632/oncotarget.17114

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Abstract

Franco Conforti1,2,*, Elizabeth R. Davies1,2,*, Claire J. Calderwood1, Thomas H. Thatcher3, Mark G. Jones1,2, David E. Smart1,2, Sumeet Mahajan4, Aiman Alzetani5, Tom Havelock2,5, Toby M. Maher6,7, Philip L. Molyneaux6,7, Andrew J. Thorley7, Teresa D. Tetley7, Jane A.­ Warner1,2,4, Graham Packham8, A. Ganesan9, Paul J. Skipp4, Benjamin J. Marshall5, Luca Richeldi1,2,5, Patricia J. Sime3, Katherine M.A. O’Reilly2,10,11 and Donna E. Davies1,2,4

1 The Brooke Laboratory, Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, University Hospital Southampton, Southampton, UK

2 NIHR Respiratory Biomedical Research Unit, University Hospital Southampton, Southampton, UK

3 Department of Medicine/Pulmonary & Critical Care, University of Rochester, Rochester, NY, USA

4 Institute for Life Sciences, University of Southampton, Highfield, UK

5 University Hospital Southampton, Southampton, UK

6 NIHR Respiratory Biomedical Research Unit, Royal Brompton Hospital, London, UK

7 National Heart & Lung Institute, Faculty of Medicine, Imperial College, London, UK

8 Cancer Sciences, University of Southampton Faculty of Medicine, University Hospital Southampton, Southampton, UK

9 School of Pharmacy, University of East Anglia, Norwich, UK

10 Respiratory Medicine, Mater Misericordiae University Hospital, Dublin, Ireland

11 School of Medicine and Medical Science, University College, Dublin, Ireland

* These authors have contributed equally to this work

Correspondence to:

Donna E. Davies, email:

Keywords: pulmonary fibrosis, histone deacetylase Inhibitors, biomarkers, myofibroblasts, epigenomics

Received: March 31, 2017 Accepted: April 03, 2017 Published: April 14, 2017

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.


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