Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2019; 25(25): 3136-3150
Published online Jul 7, 2019. doi: 10.3748/wjg.v25.i25.3136
Hepatocellular carcinoma: Therapeutic advances in signaling, epigenetic and immune targets
Daniel Neureiter, Sebastian Stintzing, Tobias Kiesslich, Matthias Ocker
Daniel Neureiter, Institute of Pathology, Cancer Cluster Salzburg, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg 5020, Austria
Sebastian Stintzing, Medical Department, Division of Oncology and Hematology, Campus Charité Mitte, Charité University Medicine Berlin, Berlin 10117, Germany
Tobias Kiesslich, Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK) and Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg 5020, Austria
Matthias Ocker, Translational Medicine Oncology, Bayer AG, Berlin 13353, Germany
Matthias Ocker, Charité University Medicine Berlin, Berlin 10117, Germany
Author contributions: All authors equally contributed to literature review, writing this paper, critical revision final approval of the final version.
Conflict-of-interest statement: Stintzing S received honoraria for talks and/or for advisory function from: Amgen, Bayer, Merck KGaA, Lilly, Sanofi, Roche, Takeda, Taiho, SIRTEX and Samsung. Ocker M is employee and shareholder of Bayer AG.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Matthias Ocker, MD, Professor, Translational Medicine Oncology, Bayer AG, Muellerstrasse 178, Berlin 13353, Germany.
Telephone: +49-30-468194799 Fax: +49-30-468994799
Received: April 6, 2019
Peer-review started: April 8, 2019
First decision: April 16, 2019
Revised: May 2, 2019
Accepted: May 18, 2019
Article in press: May 18, 2019
Published online: July 7, 2019

Hepatocellular carcinoma (HCC) remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases. Treatment of advanced disease stages is still unsatisfying. Besides first and second generation tyrosine kinase inhibitors, immune checkpoint inhibitors have become central for the treatment of HCC. New modalities like epigenetic therapy using histone deacetylase inhibitors (HDACi) and cell therapy approaches with chimeric antigen receptor T cells (CAR-T cells) are currently under investigation in clinical trials. Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers. The current status of treatment options for advanced HCC, emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.

Keywords: Liver cancer, Immunotherapy, Checkpoint inhibitors, Targeted therapy, Mouse model, Biomarker, Next-generation sequencing, Non-alcoholic steatohepatitis, Fibrosis, Clinical trial

Core tip: Treatment of advanced hepatocellular carcinoma still represents an unmet medical need. Novel therapeutic options comprise new tyrosine kinase inhibitors, epigenetic modifiers and increasingly also cell therapy and immune checkpoint inhibitors and combinations of those modalities. Development of better drugs is closely linked to improved preclinical and animal models and has to be accompanied by the implementation of predictive biomarkers, which is still lacking for hepatocellular carcinoma. The current status of these aspects is reviewed in this manuscript.