Abstract
Purpose
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 multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone.
Methods
Tumor 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 quantitatively.
Results
A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 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 Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs.
Conclusions
The results indicate that combinations of mTOR and multi-kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy.
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Acknowledgments
We 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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Pawaskar, D.K., Straubinger, R.M., Fetterly, G.J. et al. Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. Cancer Chemother Pharmacol 71, 1231–1240 (2013). https://doi.org/10.1007/s00280-013-2117-x
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DOI: https://doi.org/10.1007/s00280-013-2117-x