Recently developed strategies use molecular targeting agents specifically designed to target core regulatory signaling pathways of prostate cancers. Growth factors mediate such signaling pathways that include the PI3K/Akt/PTEN/mTOR and Ras/Raf/MEK/MAPK as well as other essential pathways. However various mitigating factors such a genetic variation, molecular diversity, diverging and converging of signaling pathways make it improbable that treatment with any single agent will result in any long-term enhanced tumor. To overcome such problems we investigated the toxicity and antitumor effects of combined targeted therapy with the mTOR inhibitor everolimus and the mulitkinase inhibitor sorafenib in a prostate-specific PTEN conditional knockout mouse model of human prostate cancer. Non-castrated and castrated (castrate-resistant prostate cancer model, CRPC) PSACre;PTENloxP/loxP mutant mice, harboring prostate tumors, were treated with everolimus and sorafenib alone or in combination for 4 weeks beginning at 16 weeks of age. All mice appeared healthy and there were no significant differences in body weights, appearance or histological findings between treatment and control groups at the end of the experiment. Our analysis shows that combination therapy has a significant additive inhibitory effect on tumor growth in non-castrate prostate cancer model (8.8 mm2, 7.7 mm2, 7.1 mm2 and 5.2 mm2 in control, everolimus, sorafenib and combination treatment groups, respectively, p=0.005). Ki67 expression was decreased and positive TUNEL apoptotic bodies was increased in combination treatment groups compared to everolimus and sorafenib monotherapy in both non-castrated and CRPC treatment groups. We also show that combination therapy, but not monotherapy, cooperated to inhibit phosphorylation of the eukaryotic translation initiation factor 4B (eIF4B). Our study provides preclinical evidence that a targeted combination treatment strategy with everolimus and sorafenib is tolerable and leads to improved treatment efficacy over single agent therapy.

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 2755. doi:1538-7445.AM2012-2755

©2012 American Association for Cancer Research
2012