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Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma

Piguet, Anne-Christine and Saar, Bettina and Hlushchuk, Ruslan and St-Pierre, Marie V. and McSheehy, Paul M. J. and Radojevic, Vesna and Afthinos, Maresa and Terracciano, Luigi and Djonov, Valentin and Dufour, Jean-François. (2011) Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma. Molecular cancer therapeutics, Vol. 10, H. 6. pp. 1007-1017.

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Official URL: http://edoc.unibas.ch/dok/A6003439

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Abstract

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor 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 (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
UniBasel Contributors:Terracciano, Luigi M.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for Cancer Research
ISSN:1535-7163
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Feb 2014 15:46
Deposited On:27 Feb 2014 15:46

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