title: Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma.
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.
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.forename: Bettina
authors.initials: B
authors.lastname: Saar
authors.forename: Ruslan
authors.initials: R
authors.lastname: Hlushchuk
authors.forename: Marie V
authors.initials: MV
authors.lastname: St-Pierre
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
authors.forename: Vesna
authors.initials: V
authors.lastname: Radojevic
authors.forename: Maresa
authors.initials: M
authors.lastname: Afthinos
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010750:Phosphoproteins / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020123:Sirolimus