Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma
- Piguet, Anne-Christine Institute for Clinical Pharmacology, University of Bern, Switzerland
- Saar, Bettina Institute for Diagnostic Radiology, Inselspital, University of Bern, Switzerland
- Hlushchuk, Ruslan Institute of Anatomy, University of Fribourg, Switzerland
- St-Pierre, Marie V. Department of Clinical Research, University of Bern, Switzerland
- McSheehy, Paul M. Oncology Research, Novartis Institute for Biomedical Research, Switzerland
- Radojevic, Vesna Institute for Clinical Pharmacology, University of Bern, Switzerland
- Afthinos, Maresa Institute of CLinical Pharmacology, University of Bern, Switzerland
- Terracciano, Luigi Institute of Pathology, Molecular Pathology Division, University of Basel, Switzerland
- Djonov, Valentin Institute of Anatomy, University of Fribourg, Switzerland
- Dufour, Jean-François Clinical Pharmacology, University of Bern, Switzerland
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12.04.2011
Published in:
- Molecular Cancer Therapeutics. - 2011, vol. 10, no. 6, p. 1007-1017
English
Sorafenib targets the Raf/mitogen activated protein kinase, VEGF and PDGF pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma cells, rats were randomly allocated to everolimus (5mg/kg, 2x/week), sorafenib (7.5mg/kg/day), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. Magnetic resonance imaging quantified tumor volumes. Erk1/2, 4E-BP1 and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85% and 55%, relative to controls, in everolimus, the combination and sequential groups, respectively (p<0.01). Survival was longest in the combination group (p<0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (p<0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.
- Faculty
- Faculté des sciences et de médecine
- Department
- Département de Médecine
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 22814
- DOI 10.1158/1535-7163.MCT-10-0666
- Persistent URL
- https://folia.unifr.ch/unifr/documents/301885
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