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

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Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development
Gastroenterology ( IF 25.7 ) Pub Date : 2021-12-22 , DOI: 10.1053/j.gastro.2021.12.250
Tongqi Qian ₁ , Naoto Fujiwara ₂ , Bhuvaneswari Koneru ₁ , Atsushi Ono ₃ , Naoto Kubota ₁ , Arun K Jajoriya ₁ , Matthew G Tung ₄ , Emilie Crouchet ₅ , Won-Min Song ₆ , Cesia Ammi Marquez ₁ , Gayatri Panda ₁ , Ayaka Hoshida ₁ , Indu Raman ₇ , Quan-Zhen Li ₇ , Cheryl Lewis ₈ , Adam Yopp ₉ , Nicole E Rich ₁ , Amit G Singal ₁ , Shigeki Nakagawa ₁₀ , Nicolas Goossens ₁₁ , Takaaki Higashi ₁₀ , Anna P Koh ₁ , C Billie Bian ₁ , Hiroki Hoshida ₁ , Parissa Tabrizian ₁₂ , Ganesh Gunasekaran ₁₂ , Sander Florman ₁₂ , Myron E Schwarz ₁₂ , Spiros P Hiotis ₁₂ , Takashi Nakahara ₃ , Hiroshi Aikata ₃ , Eisuke Murakami ₃ , Toru Beppu ₉ , Hideo Baba ₉ , Rew Warren ₁₃ , Sangeeta Bhatia ₁₃ , Masahiro Kobayashi ₁₄ , Hiromitsu Kumada ₁₄ , Austin J Fobar ₁₅ , Neehar D Parikh ₁₅ , Jorge A Marrero ₁₆ , Steve Hategekimana Rwema ₄ , Venugopalan Nair ₁₇ , Manishkumar Patel ₁₇ , Seunghee Kim-Schulze ₁₇ , Kathleen Corey ₄ , Jacqueline G O'Leary ₁₈ , Goran B Klintmalm ₁₉ , David L Thomas ₂₀ , Mohammed Dibas ₂₁ , Gerardo Rodriguez ₂₁ , Bin Zhang ₆ , Scott L Friedman ₁₇ , Thomas F Baumert ₂₂ , Bryan C Fuchs ₂₃ , Kazuaki Chayama ₂₄ , Shijia Zhu ₁ , Raymond T Chung ₄ , Yujin Hoshida ₁

Affiliation

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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.
Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, Texas.
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Division of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland.
Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.
Massachusetts Institute of Technology, Boston, Massachusetts.
Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Dallas VA Medical Center, Dallas, Texas.
Baylor Simmons Transplant Institute, Dallas, Texas.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
AbbVie, Inc, Irvine, California.
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.
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Ferring Pharmaceuticals, San Diego, California.
Collaborative Research Laboratory of Medical Innovation, Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

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.

中文翻译：

预测长期肝纤维化进展的分子特征为抗纤维化药物开发提供信息

背景与目标

由于肝纤维化进展缓慢，在临床试验中评估抗纤维化药物的预后影响存在重大未满足的需求。我们的目标是开发一种替代生物标志物来预测未来的纤维化进展。

方法

纤维化进展特征 (FPS) 被定义为预测丙型肝炎病毒和非酒精性脂肪性肝病 (NAFLD) 患者 5 年内的纤维化进展，基线时没有或极少纤维化 (n = 421)，并在独立的 NAFLD 队列中得到验证（n = 78）。FPS 用于评估临床纤维化肝组织（n = 78）的器官型离体培养物中 13 种候选抗纤维化药物的反应，以及参加临床试验的非酒精性脂肪性肝炎患者（n = 19，NCT02217475）中的 cenicriviroc。开发了一种基于血清蛋白的替代 FPS，并在一组代偿性肝硬化患者 (n = 122) 中进行了测试。

结果

在一个独立的 NAFLD 队列中定义并验证了 20 个基因的 FPS（调整后的比值比，10.93；接受者操作特征曲线下的面积，0.86）。在计算推断的纤维化驱动 FPS 基因中，BCL2使用临床肝组织被证实为潜在的药理靶点。对 13 种候选抗纤维化药物进行系统的离体评估，确定了基于表没食子儿茶素没食子酸酯的合理组合疗法，这些疗法在临床肝组织的离体培养中得到验证，可增强抗纤维化作用。在接受赛尼克里维罗治疗的非酒精性脂肪性肝炎患者中，FPS 调节与伴随 E2F 通路抑制的 1 年纤维化改善相关。没有纤维化改善的患者不存在 PPARα 通路的诱导，这表明结合 PPARα 激动作用可提高 cenicriviroc 的抗纤维化疗效。基于 7 蛋白血清蛋白的替代 FPS 与肝硬化患者失代偿的发展有关。