Tongqi Qian1, Naoto Fujiwara2, Bhuvaneswari Koneru1, Atsushi Ono3, Naoto Kubota1, Arun K Jajoriya1, Matthew G Tung4, Emilie Crouchet5, Won-Min Song6, Cesia Ammi Marquez1, Gayatri Panda1, Ayaka Hoshida1, Indu Raman7, Quan-Zhen Li7, Cheryl Lewis8, Adam Yopp9, Nicole E Rich1, Amit G Singal1, Shigeki Nakagawa10, Nicolas Goossens11, Takaaki Higashi10, Anna P Koh1, C Billie Bian1, Hiroki Hoshida1, Parissa Tabrizian12, Ganesh Gunasekaran12, Sander Florman12, Myron E Schwarz12, Spiros P Hiotis12, Takashi Nakahara3, Hiroshi Aikata3, Eisuke Murakami3, Toru Beppu9, Hideo Baba9, Sangeeta Bhatia13, Masahiro Kobayashi14, Hiromitsu Kumada14, Austin J Fobar15, Neehar D Parikh15, Jorge A Marrero16, Steve Hategekimana Rwema4, Venugopalan Nair17, Manishkumar Patel17, Seunghee Kim-Schulze17, Kathleen Corey4, Jacqueline G O'Leary18, Goran B Klintmalm19, David L Thomas20, Mohammed Dibas21, Gerardo Rodriguez21, Bin Zhang6, Scott L Friedman17, Thomas F Baumert22, Bryan C Fuchs23, Kazuaki Chayama24, Shijia Zhu25, Raymond T Chung26, Yujin Hoshida27. 1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 3. Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 4. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 5. Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France. 6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, Texas. 8. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. 9. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. 10. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 11. Division of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland. 12. Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. 13. Massachusetts Institute of Technology, Boston, Massachusetts. 14. Department of Hepatology, Toranomon Hospital, Tokyo, Japan. 15. Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan. 16. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 17. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 18. Dallas VA Medical Center, Dallas, Texas. 19. Baylor Simmons Transplant Institute, Dallas, Texas. 20. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 21. AbbVie, Inc, Irvine, California. 22. Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pole hépato-digestif, Strasbourg University Hospitals, Strasbourg, France. 23. Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Ferring Pharmaceuticals, San Diego, California. 24. Collaborative Research Laboratory of Medical Innovation, Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 25. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Shijia.Zhu@UTSouthwestern.edu. 26. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: chung.raymond@mgh.harvard.edu. 27. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Yujin.Hoshida@UTSouthwestern.edu.
Abstract
BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.
BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.
Authors: Lindsay Y King; Claudia Canasto-Chibuque; Kara B Johnson; Shun Yip; Xintong Chen; Kensuke Kojima; Manjeet Deshmukh; Anu Venkatesh; Poh Seng Tan; Xiaochen Sun; Augusto Villanueva; Angelo Sangiovanni; Venugopalan Nair; Milind Mahajan; Masahiro Kobayashi; Hiromitsu Kumada; Massimo Iavarone; Massimo Colombo; Maria Isabel Fiel; Scott L Friedman; Josep M Llovet; Raymond T Chung; Yujin Hoshida Journal: Gut Date: 2014-08-20 Impact factor: 23.059
Authors: Morten A Karsdal; Samuel J Daniels; Signe Holm Nielsen; Cecilie Bager; Daniel G K Rasmussen; Rohit Loomba; Rambabu Surabattula; Ida Falk Villesen; Yi Luo; Diane Shevell; Natasja S Gudmann; Mette J Nielsen; Jacob George; Rose Christian; Diana J Leeming; Detlef Schuppan Journal: Liver Int Date: 2020-02-19 Impact factor: 5.828
Authors: Bryan C Fuchs; Yujin Hoshida; Tsutomu Fujii; Lan Wei; Suguru Yamada; Gregory Y Lauwers; Christopher M McGinn; Danielle K DePeralta; Xintong Chen; Toshihiko Kuroda; Michael Lanuti; Anthony D Schmitt; Supriya Gupta; Andrew Crenshaw; Robert Onofrio; Bradley Taylor; Wendy Winckler; Nabeel Bardeesy; Peter Caravan; Todd R Golub; Kenneth K Tanabe Journal: Hepatology Date: 2014-02-28 Impact factor: 17.425
Authors: Emilie Crouchet; Simonetta Bandiera; Naoto Fujiwara; Shen Li; Hussein El Saghire; Mirian Fernández-Vaquero; Tobias Riedl; Xiaochen Sun; Hadassa Hirschfield; Frank Jühling; Shijia Zhu; Natascha Roehlen; Clara Ponsolles; Laura Heydmann; Antonio Saviano; Tongqi Qian; Anu Venkatesh; Joachim Lupberger; Eloi R Verrier; Mozhdeh Sojoodi; Marine A Oudot; François H T Duong; Ricard Masia; Lan Wei; Christine Thumann; Sarah C Durand; Victor González-Motos; Danijela Heide; Jenny Hetzer; Shigeki Nakagawa; Atsushi Ono; Won-Min Song; Takaaki Higashi; Roberto Sanchez; Rosa S Kim; C Billie Bian; Karun Kiani; Tom Croonenborghs; Aravind Subramanian; Raymond T Chung; Beate K Straub; Detlef Schuppan; Maliki Ankavay; Laurence Cocquerel; Evelyne Schaeffer; Nicolas Goossens; Anna P Koh; Milind Mahajan; Venugopalan D Nair; Ganesh Gunasekaran; Myron E Schwartz; Nabeel Bardeesy; Alex K Shalek; Orit Rozenblatt-Rosen; Aviv Regev; Emanuele Felli; Patrick Pessaux; Kenneth K Tanabe; Mathias Heikenwälder; Catherine Schuster; Nathalie Pochet; Mirjam B Zeisel; Bryan C Fuchs; Yujin Hoshida; Thomas F Baumert Journal: Nat Commun Date: 2021-09-17 Impact factor: 17.694
Authors: Yujin Hoshida; Augusto Villanueva; Masahiro Kobayashi; Judit Peix; Derek Y Chiang; Amy Camargo; Supriya Gupta; Jamie Moore; Matthew J Wrobel; Jim Lerner; Michael Reich; Jennifer A Chan; Jonathan N Glickman; Kenji Ikeda; Masaji Hashimoto; Goro Watanabe; Maria G Daidone; Sasan Roayaie; Myron Schwartz; Swan Thung; Helga B Salvesen; Stacey Gabriel; Vincenzo Mazzaferro; Jordi Bruix; Scott L Friedman; Hiromitsu Kumada; Josep M Llovet; Todd R Golub Journal: N Engl J Med Date: 2008-10-15 Impact factor: 91.245
Authors: Frank Jühling; Nourdine Hamdane; Emilie Crouchet; Shen Li; Bryan C Fuchs; Thomas F Baumert; Houssein El Saghire; Atish Mukherji; Naoto Fujiwara; Marine A Oudot; Christine Thumann; Antonio Saviano; Armando Andres Roca Suarez; Kaku Goto; Ricard Masia; Mozhdeh Sojoodi; Gunisha Arora; Hiroshi Aikata; Atsushi Ono; Parissa Tabrizian; Myron Schwartz; Stephen J Polyak; Irwin Davidson; Christian Schmidl; Christoph Bock; Catherine Schuster; Kazuaki Chayama; Patrick Pessaux; Kenneth K Tanabe; Yujin Hoshida; Mirjam B Zeisel; François Ht Duong Journal: Gut Date: 2020-03-26 Impact factor: 23.059