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

doi:10.18632/oncotarget.17114

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. SimeKatherine M.a. O’reilly, Donna E. Davies

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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.

Original language	English
Pages (from-to)	48737-48754
Number of pages	18
Journal	Oncotarget
Volume	8
DOIs	https://doi.org/10.18632/oncotarget.17114
Publication status	Published - 14 Apr 2017

Keywords

pulmonary fibrosis
histone deacetylase Inhibitors
biomarkers
myofibroblasts
epigenomics

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http://www.oncotarget.com/abstract/17114Licence: CC BY

A. Ganesan
- A.Ganesanuea.acuk
- School of Chemistry, Pharmacy and Pharmacology - Professor in Chemical Biology
Person: Academic, Teaching & Research

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Conforti, F., Davies, E. R., Calderwood, C. J., Thatcher, T. H., Jones, M. G., Smart, D. E., Mahajan, S., Alzetani, A., Havelock, T., Maher, T. M., Molyneaux, P. L., Thorley, A. J., Tetley, T. D., Warner, J. A. ., Packham, G., Ganesan, A., Skipp, P. J., Marshall, B. J., Richeldi, L., ... Davies, D. E. (2017). The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis. Oncotarget, 8, 48737-48754. https://doi.org/10.18632/oncotarget.17114

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title = "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.",

keywords = "pulmonary fibrosis, histone deacetylase Inhibitors, biomarkers, myofibroblasts, epigenomics",

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

year = "2017",

month = apr,

day = "14",

doi = "10.18632/oncotarget.17114",

language = "English",

volume = "8",

pages = "48737--48754",

journal = "Oncotarget",

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Conforti, F, Davies, ER, Calderwood, CJ, Thatcher, TH, Jones, MG, Smart, DE, Mahajan, S, Alzetani, A, Havelock, T, Maher, TM, Molyneaux, PL, Thorley, AJ, Tetley, TD, Warner, JA, Packham, G, Ganesan, A, Skipp, PJ, Marshall, BJ, Richeldi, L, Sime, PJ, O’reilly, KMA & Davies, DE 2017, 'The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis', Oncotarget, vol. 8, pp. 48737-48754. https://doi.org/10.18632/oncotarget.17114

TY - JOUR

T1 - The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

AU - Conforti, Franco

AU - Davies, Elizabeth R.

AU - Calderwood, Claire J.

AU - Thatcher, Thomas H.

AU - Jones, Mark G.

AU - Smart, David E.

AU - Mahajan, Sumeet

AU - Alzetani, Aiman

AU - Havelock, Tom

AU - Maher, Toby M.

AU - Molyneaux, Philip L.

AU - Thorley, Andrew J.

AU - Tetley, Teresa D.

AU - Warner, Jane A.

AU - Packham, Graham

AU - Ganesan, A.

AU - Skipp, Paul J.

AU - Marshall, Benjamin J.

AU - Richeldi, Luca

AU - Sime, Patricia J.

AU - O’reilly, Katherine M.a.

AU - Davies, Donna E.

PY - 2017/4/14

Y1 - 2017/4/14

N2 - 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.

AB - 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.

KW - pulmonary fibrosis

KW - histone deacetylase Inhibitors

KW - biomarkers

KW - myofibroblasts

KW - epigenomics

U2 - 10.18632/oncotarget.17114

DO - 10.18632/oncotarget.17114

M3 - Article

VL - 8

SP - 48737

EP - 48754

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -

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

Abstract

Keywords

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