1. 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
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