Abstract C226: CSF1R-mediated inhibition of alternatively activated macrophages to augment androgen receptor blockade therapy.

There is growing evidence for the role of inflammation in prostate cancer (PCa) progression, although the precise role of inflammation in the context of androgen ablation therapy remains unclear. Various reports demonstrate that androgen deprivation results in an increased inflammatory response in PCa and also suggest a potential role of inflammatory cells, such as macrophages and B-cells, in the acquisition of castration-resistant prostate cancer (CRPC). New PCa therapeutics have emerged showing great promise in clinical trials, such as the second generation androgen receptor (AR) antagonist MDV3100 (MDV). MDV has been shown to be more potent and effective in delaying tumor progression in CRPC patients compared to the commonly used first generation antagonist bicalutamide. However, acquired resistance to MDV has begun to emerge in preclinical models. A great deal of attention has been focused on the tumor-cell instrinsic AR bypass as the key mechanism of therapeutic resistance or failure. Few studies have explored the possible roles of tumor microenvironment in modulating therapeutic response. We and others have shown that tumor-associated macrophages (TAMs) can modulate PCa progression and therapeutic resistance. The recruitment of macrophages to and their functions in the tumor is recognized to be critically dependent on the macrophage colony-stimulating factor-1 (M-CSF-1, CSF-1), signaling through its receptor, CSF1R. Exploiting this fact, we used a selective CSF1R inhibitor, GW2580, to block TAMs influx and showed that they contribute to PCa progression and therapeutic resistance. In this current study, we observed a high level of TAMs infiltrating the CSF-1-expressing Myc-CaP murine prostate tumors. Additionally, MDV treatment further increased the level of CSF-1 expressed in tumors, further boosting the infiltration of TAMs which was reversed by GW2580. We have also observed increased expression of matrix-remodeling and pro-angiogenic factors, MMP-9 and VEGF-A in macrophages treated with conditioned media from MDV-treated Myc-CaP cells in vitro and in MDV-treated Myc-CaP tumors in vivo. These results lead us to hypothesize that blocking the CSF-1/CSF1R axis in combination with MDV anti-AR therapy, could result in synergistic anti-tumor effects. Indeed our preliminary studies indicate the combined therapies achieve slightly more effective tumor growth suppression than either of the single therapies. Our data suggest that infiltrating TAMs are alternatively activated (M2-skewed), which have been demonstrated to promote tumor growth and metastasis in many cancers. Our results suggest that TAMs in the prostatic microenvironment contribute to PCa progression and therapeutic resistance. The rational combined targeted therapy pursued here holds promise to improve the long term-efficacy of new PCa therapeutics such as MDV, and ultimately increase overall survival of prostate cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C226.