Journal article

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

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  • 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.
Faculté des sciences et de médecine
Département de Médecine
  • English
Biological sciences
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