Hepatocellular carcinoma: Therapeutic advances in signaling, epigenetic and immune targets

World J Gastroenterol. 2019 Jul 7;25(25):3136-3150. doi: 10.3748/wjg.v25.i25.3136.


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

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology
  • Disease Models, Animal
  • Drug Development
  • Drug Discovery
  • Epigenesis, Genetic / drug effects
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology
  • Molecular Targeted Therapy / methods
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Treatment Outcome


  • Antineoplastic Agents, Immunological
  • Histone Deacetylase Inhibitors
  • Protein Kinase Inhibitors