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

Abstract

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.