Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development

Tongqi Qian, Naoto Fujiwara, Bhuvaneswari Koneru, Atsushi Ono, Naoto Kubota, Arun K. Jajoriya, Matthew G. Tung, Emilie Crouchet, Won Min Song, Cesia Ammi Marquez, Gayatri Panda, Ayaka Hoshida, Indu Raman, Quan-zhen Li, Cheryl Lewis, Adam Yopp, Nicole E. Rich, Amit G. Singal, Shigeki Nakagawa, Nicolas GoossensTakaaki Higashi, Anna P. Koh, C. Billie Bian, Hiroki Hoshida, Parissa Tabrizian, Ganesh Gunasekaran, Sander Florman, Myron E. Schwarz, Spiros P. Hiotis, Takashi Nakahara, Hiroshi Aikata, Eisuke Murakami, Toru Beppu, Hideo Baba, Warren rew Warren, Sangeeta Bhatia, Masahiro Kobayashi, Hiromitsu Kumada, Austin J. Fobar, Neehar D. Parikh, Jorge A Marrero, Steve Hategekimana Rwema, Venugopalan Nair, Manishkumar Patel, Seunghee Kim-Schulze, Kathleen Corey, Jacqueline G. O'Leary, Goran B. Klintmalm, David L. Thomas, Mohammed Dibas, Gerardo Rodriguez, Bin Zhang, Scott L. Friedman, Thomas F. Baumert, Bryan C. Fuchs, Kazuaki Chayama, Shijia Zhu, Raymond T. Chung, Yujin Hoshida

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 languageEnglish (US)
Pages (from-to)1210-1225
Number of pages16
JournalGastroenterology
Volume162
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • Companion Biomarker
  • Drug Development
  • Liver Fibrosis
  • Prognostic Prediction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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