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

Piguet, Anne-Christine; Saar, Bettina; Hlushchuk, Ruslan; St-Pierre, Marie V; McSheehy, Paul M J; Radojevic, Vesna; Afthinos, Maresa; Terracciano, Luigi; Djonov, Valentin; Dufour, Jean-François (2011). Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma. Molecular cancer therapeutics, 10(6), pp. 1007-17. Philadelphia, Pa.: American Association for Cancer Research AACR 10.1158/1535-7163.MCT-10-0666

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Hlushchuk, Ruslan; Djonov, Valentin and Dufour, Jean-François

ISSN:

1535-7163

Publisher:

American Association for Cancer Research AACR

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:17

Last Modified:

06 Dec 2013 13:25

Publisher DOI:

10.1158/1535-7163.MCT-10-0666

PubMed ID:

21487053

Web of Science ID:

000291428000009

URI:

https://boris.unibe.ch/id/eprint/5134 (FactScience: 209852)

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