Abstract 3579: Sorafenib inhibits tumor development and growth in a transgenic mouse model of prostate cancer

Abstract

Abstract Background: Current estimates suggest that PI3K/Akt/mTOR signaling is upregulated in 30-50% of prostate cancers (PCa), namely through loss of Pten. Although Ras mutations in prostate cancer are infrequent, wild-type Ras is chronically activated in PCa as a result of autocrine and paracrine growth factor stimulation. More recently, it has been demonstrated that Ras activation can play a causal role in moving PCa cells towards decreased hormone dependence and an increased malignant phenotype. Sorafenib is a small molecule multikinase inhibitor that disrupts angiogenesis and blocks signaling pathways through multiple kinases, including c-Raf, that control tumor growth and progression. The purpose of this study was to evaluate the efficacy of the multi kinase inhibitor sorafenib in an autochthonous mouse model of PCa. Methods: Homozygous PSACre;PtenloxP/loxP mice were used and treated with sorafenib in chemoprevention (30 mg/kg, 3/wk for 9 or 16 wks beginning at 6 wks) and intervention (30 or 60 mg/kg 5/wk for 4 wks beginning at 16 wks) treatment protocols for androgen dependent PCa and castrate resistant prostate cancer (CRPC). Tumor size was measured by weighing the genitourinary tracts (GUT) and tumor progression was assessed by histological and computer assisted image analysis. Tumor proliferation and cell signaling was determined by immunohistochemical and/or western blot methods. Apoptosis was measured using the TUNEL method. Results: To determine the chemopreventive efficacy of sorafenib, mice were treated prior tumor development and sacrificed at time points that correlated to the different stages of tumor development (15 and 20 wks of age). Mice treated with sorafenib had significantly lower GUT weights at week 20 compared to untreated controls, (p<0.005). Moreover, mice treated with sorafenib showed a decrease in the number of PCa glands and an increase in PIN (prostatic intraepithelial neoplasia) glands compared to controls. To determine the effects of sorafenib on established tumors, mice with prostate cancer were treated with sorafenib in a dose dependent manner. Mice showed a non-significant but dose dependent reduction of GUT weight in mice treated with sorafenib. However, distribution analysis demonstrated a significant reduction of over 50% of PCa glands in sorafenib treated mice (p < 0.009). Treatment with sorafenib contributed to a 50% reduction in tumor proliferation and a 4-fold increase in apoptosis (p<0.005). In CRPC mice treated with sorafenib, a significant reduction in GUT weights, PCa glands and tumor proliferation and an increase in apoptosis were seen (p<0.01). p-Erk1/2 expression was markedly reduced in all mice treated with sorafenib when measured by immunohistochemistry and western blot. Conclusion: Taken together, these results suggest that treatment with sorafenib results in decreased prostate tumor growth and progression, particularly in tumors with Pten mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3579. doi:10.1158/1538-7445.AM2011-3579