Abstract 2930: Synergistic and additive anti-tumor effects of MIV-818 in combination with sorafenib in nonclinical hepatocellular carcinoma models
Authors: Rizoska Biljana , Bylund Johan , Briem Sveinn , Kyle Alastair , Minchinton Andrew , Öberg Fredrik , Göhlin Karin , Albertella Mark 
Published: August 2018

Abstract
Background: MIV-818, a nucleotide prodrug of troxacitabine-monophosphate, has been designed to deliver high levels of the chain-terminating nucleotide troxacitabine-triphosphate (TRX-TP) to the liver after oral dosing while minimizing systemic exposure. Sorafenib is a multikinase inhibitor with antiangiogenic and antiproliferative effects that is approved for the treatment of advanced hepatocellular carcinoma (HCC). Hypoxia is induced as a result of the antiangiogenic effects of sorafenib. Since hypoxic conditions have been shown to increase cytotoxicity of TRX via increased conversion of TRX-diphosphate to TRX-TP, we investigated the effects of combining MIV-818 or TRX with sorafenib in cell lines and in xenograft mouse models of HCC.
Methods: Synergy of MIV-818 and sorafenib was evaluated in vitro using Bliss Independence combination analysis. In vivo effects were evaluated in nude mice with subcutaneous Hep3B or HepG2 xenografts. Due to instability of MIV-818 in mouse blood, treatment with TRX was also included. MIV-818 (30 or 100 mg/kg PO) or TRX (2.5 mg/kg IP) was given twice daily for 5 days alone or in combination with sorafenib (30 mg/kg PO) once daily for 21 days. Quantitative immuno-fluorescence was used to assess DNA damage (pH2AX), proliferation (BrdU), and hypoxia (pimonidazole) in the tumors. Results: MIV-818 shows strong synergistic anti-proliferative activity with sorafenib in several HCC cell lines in vitro. In the Hep3B xenograft model, treatment with TRX or sorafenib alone resulted in tumor growth inhibition (TGI) of 32% and 52%, respectively. Combination of TRX and sorafenib was substantially more active than either agent alone, reaching a TGI of 90%. Exposures of TRX and sorafenib in plasma and tumor were similar in the combination and single agent groups, suggesting no pharmacokinetic interactions. TRX treatment resulted in significant inhibition of proliferation (by 80%) and induction of DNA damage (15-fold) in vivo. Sorafenib treatment resulted in a small but significant inhibition of proliferation (by 27%) and 3-fold induction in hypoxia, but no induction of DNA damage. The data are consistent with the expected mechanisms of action of each agent. Combination of TRX and sorafenib resulted in 92% inhibition of proliferation and induction of DNA damage (15-fold). Notably, clear responses were seen even in hypoxic regions of the tumor, which can be resistant to therapy, indicating effective delivery of TRX-TP to regions far from blood vessels. Conclusions: Additive and synergistic anti-tumor effects were observed in nonclinical HCC models after combination of MIV-818 or TRX with sorafenib. The results suggest that add-on of MIV-818 to sorafenib may be beneficial for the treatment of HCC. MIV-818 is currently in nonclinical development in preparation for clinical trials in patients with advanced HCC and other liver cancers.
Citation Format: Biljana Rizoska, Johan Bylund, Sveinn Briem, Alastair Kyle, Andrew Minchinton, Fredrik Öberg, Karin Göhlin, Mark Albertella. Synergistic and additive anti-tumor effects of MIV-818 in combination with sorafenib in nonclinical hepatocellular carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2930.