Synergistic interactions between sorafenib and eve

Authors: Dipti K Pawaskar Robert M Straubinger Gerald J Fetterly Bonnie H Hylander Elizabeth A Repasky Wen W Ma William J Jusko

Publish Date: 2013/03/03

Volume: 71, Issue: 5, Pages: 1231-1240

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Abstract

Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth We investigated whether everolimus an mTOR inhibitor and sorafenib a multikinase inhibitor would together inhibit growth of lowpassage patientderived pancreatic cancer xenografts in mice more efficaciously than either agent aloneTumor volume progression was measured following treatment with both drugs as single agents in combination and at multiple doses Pharmacokinetics in tumors and other tissues was also assessed Pharmacodynamic interactions were evaluated quantitativelyA 5week regimen of daily oral doses of 10 mg/kg sorafenib and 05 mg/kg everolimus alone and in combination did not achieve significant tumor growth inhibition Higher doses 20 mg/kg of sorafenib and 1 mg/kg of everolimus inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination Tumor volume progression was described by a linear growth model and drug effects were described by Hilltype inhibition Using population modeling approaches dualinteraction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugsWe thank Nancy Pyszczynski Ninfa Straubinger Rose Pitoniak and Yang Qu for excellent technical assistance We are grateful to The Novartis Institutes for Biomedical Research Basel Switzerland for providing everolimus for animal studies This work was supported in part by the pilot studies program of the University at Buffalo Clinical and Translational Research Center and the Buffalo Translational Consortium and by grant GM57980 from the National Institutes of Health

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