Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

Francesca Fornari,1,2 Catia Giovannini,1,3 Fabio Piscaglia,4,5 Laura Gramantieri4 1Centre for Applied Biomedical Research - CRBA, University of Bologna, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; 2Department for Life Quality Studies, University of Bologna, Rimini, Italy; 3Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; 4Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; 5Department of Medical and Surgical Sciences, University of Bologna, Bologna, ItalyCorrespondence: Laura Gramantieri; Francesca Fornari, Via Massarenti, 9, Bologna, 40138, Italy, Tel/Fax +390512143902, Email laura.gramantieri@aosp.bo.it; francesca.fornari2@unibo.itAbstract: In the last decade, relevant advances have occurred in the treatment of hepatocellular carcinoma (HCC), with novel drugs entering the clinical practice, among which tyrosine kinase inhibitors (TKIs) such as lenvatinib, cabozantinib and regorafenib, and immune checkpoint inhibitors (ICPIs) either alone or in combination with VEGF inhibitors. Clinical trials have driven the introduction of such novel molecules into the clinics but, at present, no biomarker drives the choice of first-line options, which relies only upon clinical and imaging assessment. Remarkably, clinical and imaging-based evaluations do not consider the huge heterogeneity of HCC and do not allow to realize the potential of personalized treatments. Preclinical research still does not inform the design of clinical trials, even though many animal models mimicking specific subgroups of HCC are available and might provide relevant information. Although animal models directly informing the clinical practice, such as patients-derived xenografts, are not used to help the choice of treatment in advanced HCC, however, the preclinical research can count on a wide range of valuable models. Here we will review some HCC models which might turn informative for specific questions in defined patient subgroups, and we will describe recent preclinical studies for the mechanistic evaluation of immunotherapy-based treatment approaches. To this aim, we will mainly focus on two issues: (i) HCC models informative on NAFLD-NASH HCC and (ii) HCC models helping to elucidate mechanisms underneath immunotherapy. We have chosen these two settings since they represent, respectively, the most rapidly arising cause of chronic liver disease (CLD) and HCC in western countries and the most promising therapeutic option for advanced HCC.Keywords: HCC, NASH, animal models, treatments, immunotherapy, TKIs