Abstract 3681: Multi-scale analysis of everolimus and sorafenib combination in pancreatic cancer xenografts
Authors: Pawaskar Dipti K. , Straubinger Robert M. , Fetterly Gerald , Hylander Bonnie H. , Repasky Elizabeth A. , Ma Wen W. , Jusko William J. 
Published: August 2012

Abstract
Objective: To investigate factors impacting efficacy of combined regimen of the molecularly targeted agents everolimus and sorafenib in pancreatic cancer (PaCA) xenografts. Rationale: Everolimus inhibits mTOR (mammalian target of rapamycin) that drives cell proliferation, cell survival and angiogenesis. Sorafenib is a multikinase inhibitor of cell growth and angiogenic pathways driving tumor progression. By inhibiting compensatory pathways, combinations of these drugs could improve efficacy in pancreatic cancer. Methods: SCID mice were implanted sc with low-passage, patient-derived pancreatic adenocarcinomas. Groups of 9 animals were dosed by oral gavage for 5 weeks with individual drugs or combinations. Low-dose groups received 0.5 mg/kg everolimus/10 mg/kg sorafenib, and high-dose groups received 1 mg/kg everolimus/20 mg/kg sorafenib. These doses were selected by preliminary scaling of expected human plasma drug exposures in an ongoing Phase I trial, as well as prior data for the drugs individually on cell-line based PaCA xenografts. Tumor volume progression and body weight were the primary pharmacodynamic (PD) endpoints. Pharmacokinetics (PK) was evaluated from plasma, tumor and tissue concentrations of drug in naïve animals or during the 24 h following the last dose of week 5. Scalable, physiologically- based PK (PBPK) models were developed for each drug, which enabled inter- species comparison of plasma drug exposures. A mechanistic PD model based on tumor growth and inhibition by the drugs was developed to relate PK to the observed PD endpoints. Results: Neither drug alone or in combination had significant effects on tumor progression at lower doses regimen. At higher doses, each inhibited tumor growth by 70 %, and the combination caused complete (100%) inhibition. The PBPK models well described everolimus and sorafenib concentrations in plasma, tissues and tumor. The model was extended to capture the PD and was able to describe the observed tumor suppression data. Drug exposures expected in a Phase 1 trial of the drugs were calculated for equivalent scaled doses. The lower, inefficacious doses resulted everolimus exposures 2-fold lower than in mice and 2-fold higher for sorafenib. At the higher, efficacious doses, everolimus was approx. 4-fold higher than expected in humans and the sorafenib exposures were similar in mice and humans. Conclusions: Combined inhibition of the mTOR and multiple kinase pathways can improve the efficacy of molecularly targeted agents in SCID mouse models of PaCA. Development of multiscale, linked PK and PD models provides a quantitative approach to compare efficacy of drug combination strategies in murine human tumor explants and provide insights that support clinical trials of molecularly targeted agents in advanced malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3681. doi:1538-7445.AM2012-3681