Abstract 4485: Everolimus reduces androgen dependent and independent prostate cancer in the prostate specific PTEN conditional gene targeting mouse model
Authors: De Velasco Marco A. , Asahi Chiori , Miyazaki Yuka , Ushida Hiroshi , Shimada Keiji , Yoshikawa Kazuhiro , Nishio Kazuto , Konishi Noboru , Uemura Hirotsugu 
Published: February 2011

Abstract
PTEN deletion is common in castrate resistant prostate cancer (CRPC) with bi-allelic loss correlating to disease-specific mortality and is associated with Akt and AR deregulation. Due to the lack of effective treatment options, new targets for chemotherapy need to be identified. The PI3K/AKT/mTOR pathway is an attractive target and mTOR is one of the most focused targets for small molecule inhibitors. We investigated the treatment efficacy of the mTOR inhibitor, everolimus alone or in combination with the androgen agonist chlormadinone acetate (CA) on non-CRPC and CRPC using our prostate specific PTEN conditional gene targeting mouse model. Sixteen-week-old mice were gavaged with everolimus (10 mg/kg 3x/week) and/or injected subcutaneously with CA (50 mg/kg 3X/week) for 4 weeks. For the CRPC model, mice were castrated at 8 weeks of age and then gavaged with everolimus for 4 weeks starting at 16 weeks of age. The genitourinary tracts (GUTs), were collected, weighed, and imaged. GUT weights were significantly lower in all treatments groups compared to controls in the non-CRPC model (P&lt;0.01) but not in the CRPC model. Morphometric image analysis performed on the GUT to measure the prostate area revealed significant shrinkage of the prostate in the treatment groups vs. the corresponding controls in both models (P&lt;0.005). Histopathological distribution analysis of normal, prostatic intraepithelial neoplasia (PIN) and tumor glands a revealed a significant reduction of cancer glands in mice treated with everolimus, CA or combination compared to control intact mice or castrated mice (P&lt;0.004, P&lt;0.05, respectively). Furthermore, the ratio of normal: cancer increased from 0.33 in untreated controls to 1.13, 0.66 and 0.80 in everolimus, CA and combination treatment mice, respectively. No differences were noted in ratios between normal: PIN and PIN: cancer between these groups. In the castrate resistant model, increases were seen in the ratios of normal: cancer and PIN: cancer if everolimus-treated mice vs. untreated controls (0.22 vs. 0.41 and 0.22 vs. 0.60, respectively). The suppressive effect of everolimus treatment was confirmed by the suppression PS6K and increased p4EBP1 expression in both, non-castrated and castrated mice. Mice treated with CA also showed decreased nuclear expression of androgen receptor. Our data suggests that treatment with everolimus results in decreased tumor growth and progression and that this effect is enhanced with androgen ablation therapy. These findings indicate that treatment with everolimus may be effective against CRPC and the treatment results may be enhanced by the combination of anti-androgen therapy in patients with non-CRPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4485.