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.
Highlights
Sorafenib is the only drug for which randomized control trials have shown an improved survival in advanced hepatocellular carcinoma (HCC; refs. 1, 2), and is the only systemic targeted therapy approved for clinical use in many countries
The median survival was longest for the combined everolimus–sorafenib group (70 days, P < 0.001 vs. control and sorafenib groups), shorter for sorafenib monotherapy (63.5 days), and shortest for the controls (57 days; Fig. 1C)
We previously reported that inhibition of the mTOR pathway, which is activated in many cases of HCC [11,12,13], decreases VEGF levels, impairs tumor angiogenesis, and results in smaller tumors and longer survival in a rat Morris Hepatoma (MH)-3924A model of HCC [6]
Summary
Sorafenib is the only drug for which randomized control trials have shown an improved survival in advanced hepatocellular carcinoma (HCC; refs. 1, 2), and is the only systemic targeted therapy approved for clinical use in many countries. Sorafenib inhibits the kinase activity of Raf, an enzyme operative within the mitogen-activated protein kinase (MAPK) signaling pathway and inhibits the VEGF receptors (VEGFR) and platelet-derived. Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). As a result of the inhibition of these target molecules, sorafenib decreases tumor microvessel density and exerts an antiproliferative effect on tumor cells [4]. Despite these actions, sorafenib only extends the life expectancy of patients with HCC by a few months, suggesting that other signaling pathways remain active
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