Abstract B129: Preclinical assessment of targeting insulin-like growth factor-2 in bone metastasis from prostate cancer by a human neutralizing antibody (m610) and human adult bone implanted model

Abstract

Abstract Background: Insulin-like growth factor (IGF)-2 activates IGF-1 receptor (IGF-1R) as well as insulin receptor (IR). Recently, it is becoming increasingly evident that IR activation by IGF-2 enhances the growth of neoplasms such as Ewing sarcoma and breast cancer in addition to the IGF-1R activation. Advanced prostate cancer frequently and organ-specifically metastasizes to the bone, where the IGF-2 is abundant. However, the role of IGF-2 in bone metastasis from prostate cancer is still uncertain. The present study was aimed at exploring the role of IGF-2 in the growth of prostate cancer cells in a human bone environment and the therapeutic potential of inhibiting IGF-2 by a neutralizing antibody in the bone metastasis. Materials and Methods: Using our human neutralizing antibody to IGF-2 (m610) and human adult bone implanted mouse model, we investigated whether inhibiting IGF-2 suppresses the growth of prostate cancer cells in the human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of NOD/SCID mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells. At 4 weeks after the treatments, histological analyses of the obtained specimens were performed. Results: M610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. M610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. IGF-1R and IR expressions on the MDA PCa 2b tumors were confirmed by immunostaining. M610 prevented in vitro IGF-2-induced cell proliferation, phosphorylation of the receptors and phosphorylation of Akt in MDA PCa 2b cells. Conclusions: These results demonstrate that IGF-2 plays a crucial role in the prostate cancer cell growth in human bone. Targeting IGF-2 by neutralizing antibodies would be a promising therapeutic approach to preventing bone metastasis from prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B129.