Oncopig and human hepatocellular carcinoma cell lines exhibit similar response to liver cancer chemotherapy agents

M.F. Neto, H.H. Chen, J. Newson, L.B. Schook, K.M. Schachtschneider, R.C. Gaba
American Association for Cancer Research Annual Meeting, April 14-18 2018, Chicago, IL

Preclinical animal models represent pivotal tools to develop novel therapeutics. While murine models are commonly used in preclinical drug research, many agents that show promise in mouse studies ultimately fail in human clinical trials. In contrast to mice, pigs share many genetic, physiological, and metabolic similarities with humans, which may facilitate relevant investigation of drug pharmacokinetic and therapeutic analyses. The Oncopig Cancer Model (OCM) is a novel transgenic swine platform that recapitulates human cancer through development of site/cell specific tumors after Cre recombinase induced expression of heterozygous KRASG12D and TP53R167H transgenes. Given similar drug metabolism between pigs and humans, we propose that the OCM can address unmet clinical needs by facilitating translation of results obtained in preclinical murine studies to human clinical practice. In order to investigate the feasibility of using the OCM for drug screening, we tested the hypothesis that OCM and human hepatocellular carcinoma (HCC) cell lines exhibit similar responses to chemotherapy agents commonly used in clinical settings. Responses to four cytostatic (sorafenib) and cytotoxic (doxorubicin, cisplatin, mitomycin C) HCC chemotherapies were compared between OCM derived porcine HCC cell lines and three representative human HCC cell lines (SNU-387, SNU-475, HepG2). Results of MTT time course assays (3x performance) revealed that OCM HCC and human HCC cell lines displayed similar sensitivities to all four chemotherapies when exposed to comparable, clinically relevant concentrations for 72 hours. Sorafenib had a cytostatic effect at 10-20 µM in all four cells lines tested, consistent with clinically relevant, 3-15 µM systemic therapeutic concentrations. Doxorubicin, usually administered at 1-5 µM for locoregional therapy in patients, had comparable half maximal inhibitory concentrations (IC50) for pHCC (0.19 µM), HepG2 (0.45 µM), and SNU-387 (0.94 µM), but was higher for SNU-475 (3.31 µM). Mitomycin C had similar IC50 for pHCC (1.77 µM), HepG2 (1.73 µM), and SNU-475 (2.93 µM), but was higher for SNU-387 (7.91 µM). Finally, IC50 for cisplatin was nearly identical for pHCC (7.54 µM) and HepG2 (8.34 µM), but higher for SNU-387 (25.89 µM) and SNU-475 (16.57 µM). These results show clinically relevant similarities in response to the tested chemotherapy agents between pHCC and HepG2 (the most widely used human HCC cell line for in vitro investigations). Notably, differential drug responses observed between human HCC cell lines are consistent with previous studies, and are likely reflective of differential pathway alterations driving oncogenesis in these lines. These results indicate the OCM represents a valuable tool for screening promising chemotherapy agents, providing a novel large animal bridge between preclinical investigation in small animal models and human clinical trials.