Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma

Huynh, Hung; Ngo, Van Chanh; Koong, Heng Nung; Poon, Dennis; Choo, Su Pin; Thng, Choon Hua; Chow, Pierce K. H.; Ong, Hock Soo; Chung, Alexander Yaw Fui; Soo, Khee Chee

doi:10.1111/j.1582-4934.2009.00692.x

Cited by 114 publications

(86 citation statements)

References 40 publications

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“…Our positive results contrast with those of Newell and colleagues, who found no difference in tumor growth with this combination (14). This disparity is perhaps explained by our propitious choice of an orthotopic syngeneic model, which is a closer representation of HCC than the xenograft model chosen by previous investigators (7,14,15) HCC is a hypervascular tumor, relying on angiogenesis for growth (16). Focal hypoxia is a potent angiogenic stimulus and both everolimus and sorafenib treatment regimens exerted their antitumoral effects within a local environment that was subject to such stimuli, as shown by the increased expression of HIF-1a in all treated tumors (Fig.…”

Section: Discussioncontrasting

confidence: 57%

“…As the activities of mTOR inhibitors and sorafenib occur at separate stages along 2 signaling pathways, their combination could be complementary and provide more effective suppression of HCC. Although the combination of sorafenib and rapamycin has shown synergistic inhibition of HCC xenografts (7), important information is lacking with respect to the mechanisms of this synergism and the specific effects of the drug combination on angiogenic processes. Additional uncertainties relate to the most effective means of administering the drug combination and whether patients who have been unresponsive or intolerant to sorafenib could subsequently benefit from an mTOR inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Piguet

Saar

Hlushchuk

et al. 2011

Molecular Cancer Therapeutics

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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, 2Â/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.

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Section: Discussioncontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Piguet

Saar

Hlushchuk

et al. 2011

Molecular Cancer Therapeutics

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“…Second, because signaling pathways are integrated, inhibition of one may potentially activate others. This has been proven by recent studies, where the inhibition of the Ras/Raf/MAPK pathway by sorafenib simultaneously increased the phosphorylation of mTOR and the activation of the PI3K/AKT/mTOR pathway, which is critical for the development and proliferation of HCC (Strumberg, 2005;Huynh et al, 2009;Gedaly et al, 2010). As a result, continuous sorafenib administration may upregulate pathways, such as the PI3K/AKT/mTOR pathway, as a compensatory mechanism.…”

Section: Discussionmentioning

confidence: 85%

Sorafenib Continuation after First Disease Progression Could Reduce Disease Flares and Provide Survival Benefits in Patients with Hepatocellular Carcinoma: a Pilot Retrospective Study

Zhang²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Considering the existing crosstalk between the PI3K/Akt and MAPK pathways [20] , the latent compensatory mechanism of PI3K/Akt pathways in drug resistance to sorafenib has been attracting attention. Sorafenib has been demonstrated to activate Akt and upregulate the phosphorylation of its downstream targets, such as S6K and 4EBP1 in HCC cells [21,22] . A study by Chen et al [7] has shown that sorafenib-resistant HCC cells, which were established by long-term exposure to sorafenib, had increased expression of phosphorylated Akt and p85, a regulatory subunit of PI3K, compared with the parental cells.…”

Section: Pi3k/akt Pathway and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

157

148

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma

Cited by 114 publications

References 40 publications

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Sorafenib Continuation after First Disease Progression Could Reduce Disease Flares and Provide Survival Benefits in Patients with Hepatocellular Carcinoma: a Pilot Retrospective Study

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

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