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Published on: January 19, 2019
Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice
Dipti K Pawaskar1, Robert M Straubinger, Gerald J Fetterly
1Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA.
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.
Insights
Combining mTOR and multi-kinase inhibitors shows synergistic effects against pancreatic cancer xenografts. Higher doses of everolimus and sorafenib together completely inhibited tumor growth, suggesting enhanced efficacy for pancreatic cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeted cancer therapies often face challenges due to compensatory survival pathways.
- Pancreatic cancer remains a significant therapeutic challenge, necessitating novel treatment strategies.
Purpose of the Study:
- To investigate the combined efficacy of everolimus (an mTOR inhibitor) and sorafenib (a multi-kinase inhibitor) against pancreatic cancer.
- To test the hypothesis that inhibiting compensatory pathways with drug combinations is more effective than single agents.
Main Methods:
- Utilized low-passage, patient-derived pancreatic cancer xenografts in mice.
- Administered sorafenib and everolimus as single agents and in combination at multiple doses.
- Assessed tumor volume progression, pharmacokinetics, and pharmacodynamic interactions.
Main Results:
- Lower doses showed limited tumor growth inhibition, but higher doses of both agents significantly inhibited growth individually.
- The combination of higher doses of sorafenib and everolimus resulted in complete inhibition of tumor growth.
- Population modeling revealed a highly synergistic pharmacodynamic interaction between the two drugs.
Conclusions:
- Combination therapy with mTOR and multi-kinase inhibitors demonstrates superior efficacy in pancreatic cancer models compared to monotherapy.
- Potential contribution of drug effects on tumor stromal elements to enhanced anti-tumor activity.
