Combination treatment by AKT inhibitor ARQ 092 and Sorafenib

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Combination treatment by AKT inhibitor ARQ 092 and Sorafenib in a cirrhotic rat model with hepatocellular carcinoma Zuzana Macek Jilkova1,2, Ayca Zeybek Kuyucu1,2, Keerthi Kurma1,2, Séyédéh Tayébéh Ahmad Pour1,2, Gaël S Roth1,2,3, Giovanni Abbadessa4, Yi Yu4, Vincent Leroy1,2,3, Patrice Marche1,2 and Thomas Decaens1,2,3 1Université Grenoble Alpes; 2Institute for Advanced Biosciences, Research Center UGA / Inserm U 1209 / CNRS 5309; 3 Clinique Universitaire d’Hépato-gastroentérologie,CHU Grenoble, France; 4ArQule Inc, USA Background METHODS RESULTS - in vivo Hepatocellular carcinoma is the 5th most common cancer worldwide and the 2nd cancer related death Developed on cirrhosis in 90% of the cases Only one approved drug in advanced cases: sorafenib PI3K/AKT/mTOR pathway activated in HCC >50% of the cases and in fibrogenesis in vitro - Cell viability and migration was tested on HepG2, Hep3B, HUH7, PLC/PRF5 Tumor progression assessed by MRI Number and size of tumors on liver surface Cell proliferation in tumor tissue in vivo - Treatment protocol Antiangiogenic effect Fibrosis assessed by Sirius red Oral gavage daily: Sorafenib (10 mg/kg) continuously ARQ 092 (15 mg/kg) 5 days ON/ 9 days OFF OBJECTIVES Benefit < 3 months ARQ 092 T2-weighted MRI: diameter of 10 largest tumors (representative image of control rat) Pathway analysis Western blot qPCR RESULTS - in vitro Synergistic suppression of cell growth (Hep3B, MTT)* Reduced migration in additive manner (Hep3B, Scratch assay)* CONCLUSIONS Combination of Sorafenib and ARQ 092 exerted additive effect in controlling tumor progression, reduced angiogenesis and improved liver fibrosis. Our results confirm the importance of targeting AKT in hepatocellular carcinoma. *Similar results were obtained with HepG2, HUH7 and PLC/PRF5 Contact: tdecaens@chu-grenoble.fr, zuzana.macek-jilkova@inserm.fr Printed by