Poster

publicité
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
METHODS
BACKGROUND
RESULTS - in vivo
• Hepatocellular carcinoma is the 5th most common
cancer worldwide and the 2nd cancer related death
in vitro - Cell viability and migration was tested on HepG2,
• Developed on cirrhosis in 90% of the cases
in vivo - Treatment protocol
Hep3B, HUH7, PLC/PRF5
• Tumor progression
assessed by MRI
• Number and size of tumors
on liver surface
• Cell proliferation
in tumor tissue
• Only one approved drug in advanced cases:
sorafenib
• PI3K/AKT/mTOR pathway activated in HCC >50%
of the cases and in fibrogenesis
• Antiangiogenic effect
• Oral gavage daily:
Sorafenib (10 mg/kg) continuously
ARQ 092 (15 mg/kg) 5 days ON/ 9 days OFF
OBJECTIVES
• T2-weighted MRI:
diameter of 10
largest tumors
(representative
image of control rat)
• Fibrosis assessed by Sirius red
• Pathway analysis
Western blot
ARQ 092
Benefit < 3
months
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.
*Similar results were obtained with HepG2, HUH7 and PLC/PRF5
Contact: [email protected], [email protected]
• Our results confirm the importance of targeting AKT in hepatocellular carcinoma.
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