RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

Abstract

Introduction mTOR activity is increased in advanced prostate cancer (CaP) as a result of a high rate of PTEN mutations. RAD001 (Everolimus) is a new orally available mTOR inhibitor. The objective of our study was to evaluate the effects of RAD001 on the growth of CaP in the bone, both alone and in combination with docetaxel and zoledronic acid. Methods C4‐2 CaP cells were injected into tibiae of mice and the animals were treated with RAD001, docetaxel, and zoledronic acid alone or in combination. Histomorphometrical analysis, serum PSA measurements, bone mineral density (BMD), and µCT were used to determine the effects of treatment on tumor and bone. Results All three agents alone decreased tumor volume, and RAD001 and docetaxel also decreased levels of serum PSA by 68% and 65%, respectively (both P < 0.01). Combinations of the agents were more effective in decreasing tumor volume than single agents. Three‐drug treatment showed the greatest effect: 64% inhibition versus control (P < 0.01). Treatment with RAD001 interfered with the weight loss associated with growth of this tumor in the bone (non‐RAD001 groups: 4.0% decrease in body weight, P = 0.0014; RAD001 groups: increase of 3.6% in body weight, P = 0.0037). Conclusions RAD001 inhibited growth of C4‐2 cells in bone, an effect augmented by addition of docetaxel and zoledronic acid. Moreover RAD001 had a significant impact on maintenance of body weight. RAD001 may hold promise for its effects on both metastatic CaP and the important syndrome of tumor cachexia. Prostate 68:861–871, 2008.