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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1210-1225 |
| Number of pages | 16 |
| Journal | Gastroenterology |
| Volume | 162 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
Keywords
- Companion Biomarker
- Drug Development
- Liver Fibrosis
- Prognostic Prediction
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development. / Qian, Tongqi; Fujiwara, Naoto; Koneru, Bhuvaneswari et al.
In: Gastroenterology, Vol. 162, No. 4, 04.2022, p. 1210-1225.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development
AU - Qian, Tongqi
AU - Fujiwara, Naoto
AU - Koneru, Bhuvaneswari
AU - Ono, Atsushi
AU - Kubota, Naoto
AU - Jajoriya, Arun K.
AU - Tung, Matthew G.
AU - Crouchet, Emilie
AU - Song, Won Min
AU - Marquez, Cesia Ammi
AU - Panda, Gayatri
AU - Hoshida, Ayaka
AU - Raman, Indu
AU - Li, Quan Zhen
AU - Lewis, Cheryl
AU - Yopp, Adam
AU - Rich, Nicole E.
AU - Singal, Amit G.
AU - Nakagawa, Shigeki
AU - Goossens, Nicolas
AU - Higashi, Takaaki
AU - Koh, Anna P.
AU - Bian, C. Billie
AU - Hoshida, Hiroki
AU - Tabrizian, Parissa
AU - Gunasekaran, Ganesh
AU - Florman, Sander
AU - Schwarz, Myron E.
AU - Hiotis, Spiros P.
AU - Nakahara, Takashi
AU - Aikata, Hiroshi
AU - Murakami, Eisuke
AU - Beppu, Toru
AU - Baba, Hideo
AU - rew Warren, Warren
AU - Bhatia, Sangeeta
AU - Kobayashi, Masahiro
AU - Kumada, Hiromitsu
AU - Fobar, Austin J.
AU - Parikh, Neehar D.
AU - Marrero, Jorge A.
AU - Rwema, Steve Hategekimana
AU - Nair, Venugopalan
AU - Patel, Manishkumar
AU - Kim-Schulze, Seunghee
AU - Corey, Kathleen
AU - O'Leary, Jacqueline G.
AU - Klintmalm, Goran B.
AU - Thomas, David L.
AU - Dibas, Mohammed
AU - Rodriguez, Gerardo
AU - Zhang, Bin
AU - Friedman, Scott L.
AU - Baumert, Thomas F.
AU - Fuchs, Bryan C.
AU - Chayama, Kazuaki
AU - Zhu, Shijia
AU - Chung, Raymond T.
AU - Hoshida, Yujin
N1 - Funding Information: Funding This study was partially supported by a research fund from AbbVie (for the ex vivo tissue culture with cenicriviroc and hepatic transcriptome profiling of patients with nonalcoholic steatohepatitis enrolled in the CENTAUR trial), which did not have any role in the collection, analysis, and interpretation of data. This research was supported by the Uehara Memorial Foundation (to Naoto Fujiwara and Shigeki Nakagawa); the FLAGS Foundation; the Nuovo-Soldati Cancer Research Foundation; an advanced training grant from Geneva University Hospital (to Nicolas Goossens); US National Institutes of Health DK099558 and CA233794 (to Yujin Hoshida), CA142543 (to Cheryl Lewis), DK56621 and DK128289 (to Scott L. Friedman), and DA013806 (to David L. Thomas); the Irma T. Hirschl Trust (to Yujin Hoshida); European Commission ERC-2014-AdG-671231 (to Thomas F. Baumert and Yujin Hoshida); US Department of Defense W81XWH-16-1-0363 (to Yujin Hoshida); Cancer Prevention and Research Institute of Texas RR180016 (to Yujin Hoshida), Association for Cancer Research Paris and Institut Hospitalo-Universitaire Strasbourg IHUARC2019 (to Thomas F. Baumert); Japan Agency for Medical Research and Development JPfk0210090 (to Kathleen Corey); and the Massachusetts General Hospital Research Scholars Program (to Raymond T. Chung). Funding Information: Yujin Hoshida, MD, PhD (Formal analysis: Equal; Funding acquisition: Lead; Project administration: Lead; Supervision: Lead; Writing – original draft: Lead; Writing – review & editing: Equal); Tongqi Qian, MPH (Data curation: Equal; Formal analysis: Lead; Methodology: Equal; Validation: Equal; Visualization: Lead; Writing – original draft: Equal; Writing – review & editing: Equal); Naoto Fujiwara, MD, PhD (Formal analysis: Lead; Investigation: Equal; Methodology: Equal; Validation: Equal; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Equal); Bhuvaneswari Koneru, PhD (Formal analysis: Lead; Investigation: Equal; Project administration: Supporting; Resources: Equal; Visualization: Equal; Writing – original draft: Lead; Writing – review & editing: Equal); Atsushi Ono, MD, PhD (Data curation: Equal; Formal analysis: Lead; Investigation: Equal; Resources: Equal; Validation: Supporting; Visualization: Equal; Writing – original draft: Lead; Writing – review & editing: Equal); Naoto Kubota, MD, PhD (Investigation: Supporting; Validation: Supporting; Visualization: Supporting; Writing – review & editing: Supporting); Arun K. Jajoriya, PhD (Investigation: Supporting; Validation: Supporting); Matthew G. Tung, MD (Investigation: Supporting; Resources: Supporting); Emilie Crouchet, PhD (Investigation: Supporting); Won-Min Song, PhD (Software: Equal); Cesia Ammi Marquez, BS (Investigation: Supporting); Gayatri Panda, MS (Investigation: Supporting; Project administration: Supporting); Ayaka Hoshida, BS (Investigation: Supporting); Cheryl Lewis, PhD (Resources: Supporting); Adam Yopp, MD (Resources: Supporting); Nicole Rich, MD (Resources: Supporting); Amit G Singal, MD, MS (Resources: Supporting; Writing – review & editing: Supporting); Shigeki Nakagawa, MD, PhD (Investigation: Supporting); Nicolas Goossens, MD, PhD (Investigation: Supporting; Writing – review & editing: Supporting); Takaaki Higashi, MD, PhD (Investigation: Supporting); Anna P. Koh, PhD (Investigation: Supporting); C. Billie Bian, BS (Investigation: Supporting); Hiroki Hoshida, BS (Investigation: Supporting); Parissa Tabrizian, MD (Resources: Supporting); Ganesh Gunasekaran, MD (Resources: Supporting); Sander Florman, MD (Resources: Supporting); Myron E. Schwarz, MD (Resources: Supporting); Spiros P. Hiotis, MD (Resources: Supporting); Takashi Nakahara, MD (Resources: Supporting); Hiroshi Aikata, MD (Resources: Supporting); Eisuke Murakami, MD (Resources: Supporting); Toru Beppu, MD (Resources: Supporting); Hideo Baba, MD (Resources: Supporting); Andrew Warren, PhD (Resources: Supporting); Sangeeta Bhatia, MD, PhD (Resources: Supporting); Masahiro Kobayashi, MD (Resources: Supporting); Hiromitsu Kumada, MD (Resources: Supporting); Steve Hategekimana Rwema, MD (Resources: Supporting); Venugopalan Nair, PhD (Investigation: Supporting); Manishkumar Patel, MA (Investigation: Supporting); Seunghee Kim-Schulze, PhD (Investigation: Supporting); Kathleen Corey, MD (Data curation: Equal; Resources: Equal); Jacqueline G. O'Leary, MD (Data curation: Equal; Resources: Equal; Writing – review & editing: Supporting); Goran B. Klintmalm, MD, PhD (Data curation: Equal; Resources: Equal); David L. Thomas, MD, PhD (Data curation: Equal; Resources: Equal; Writing – review & editing: Supporting); Mohammed Dibas, PhD (Funding acquisition: Supporting; Resources: Supporting); Gerardo Rodriguez, PhD (Funding acquisition: Supporting; Resources: Supporting); Bin Zhang, PhD (Software: Equal); Scott L. Friedman, MD (Funding acquisition: Supporting; Writing – review & editing: Supporting); Thomas Baumert, MD (Funding acquisition: Supporting; Supervision: Equal; Writing – review & editing: Supporting); Bryan C. Fuchs, PhD (Investigation: Supporting; Writing – review & editing: Supporting); Kazuaki Chayama, MD (Supervision: Equal; Writing – review & editing: Supporting); Shijia Zhu, PhD (Project administration: Equal; Supervision: Equal; Writing – review & editing: Equal); Raymond T. Chung, MD (Project administration: Equal; Resources: Supporting; Supervision: Equal; Writing – review & editing: Equal); Indu Raman, MS (Investigation: Supporting); Quan-Zhen Li, MD, PhD (Investigation: Supporting); Austin Fobar, MS (Resources: Supporting); Neehar Parikh, MD (Resources: Supporting); Jorge Marrero, MD (Resources: Supporting) Funding This study was partially supported by a research fund from AbbVie (for the ex vivo tissue culture with cenicriviroc and hepatic transcriptome profiling of patients with nonalcoholic steatohepatitis enrolled in the CENTAUR trial), which did not have any role in the collection, analysis, and interpretation of data. This research was supported by the Uehara Memorial Foundation (to Naoto Fujiwara and Shigeki Nakagawa); the FLAGS Foundation; the Nuovo-Soldati Cancer Research Foundation; an advanced training grant from Geneva University Hospital (to Nicolas Goossens); US National Institutes of Health DK099558 and CA233794 (to Yujin Hoshida), CA142543 (to Cheryl Lewis), DK56621 and DK128289 (to Scott L. Friedman), and DA013806 (to David L. Thomas); the Irma T. Hirschl Trust (to Yujin Hoshida); European Commission ERC-2014-AdG-671231 (to Thomas F. Baumert and Yujin Hoshida); US Department of Defense W81XWH-16-1-0363 (to Yujin Hoshida); Cancer Prevention and Research Institute of Texas RR180016 (to Yujin Hoshida), Association for Cancer Research Paris and Institut Hospitalo-Universitaire Strasbourg IHUARC2019 (to Thomas F. Baumert); Japan Agency for Medical Research and Development JPfk0210090 (to Kathleen Corey); and the Massachusetts General Hospital Research Scholars Program (to Raymond T. Chung). Publisher Copyright: © 2022 AGA Institute
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - Companion Biomarker
KW - Drug Development
KW - Liver Fibrosis
KW - Prognostic Prediction
UR - http://www.scopus.com/inward/record.url?scp=85125765695&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125765695&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.12.250
DO - 10.1053/j.gastro.2021.12.250
M3 - Article
C2 - 34951993
AN - SCOPUS:85125765695
SN - 0016-5085
VL - 162
SP - 1210
EP - 1225
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -