*5.1. CCL2-CCR2 Axis*

A new role for AR silencing in the mediation of EMT induction via activation of the CCL2-CCR2 axis in the tumor microenvironment provides new therapeutic targets for preventing potential prostate cancer metastasis at later stages. A previous study reported on treatment of forty-six CRPC patients with the human CCL2 monoclonal antibody, carlumab, in a phase 2 trial. Unfortunately, this single-arm study was not able to meet its primary objective to demonstrate potential therapeutic benefits of carlumab alone in patients with metastatic CRPC who had failed prior docetaxel-based treatment [39]. Carlumab was unable to sustain durable free CCL2 suppression, permitting rapid rebound and increases in CCL2 to baseline or higher concentrations; this insufficient suppression meant meaningful clinical responses could not be achieved [39]. To entirely suppress the CCL2-CCR2 axis, a receptor antagonist may provide a more suitable treatment method as receptor blockade efficiency is irrespective of serum CCL2 concentrations. Several CCR2 antagonists has been reported in the literature [40,41]. As stated in Section 2, CCL2-CCR2 axis and STAT3 activate each other in prostate cancer cells, therefore STAT3 is also regarded as a potential treatment target. We confirmed inhibition of STAT3 activity by a STAT3 inhibitor, AG490, resulted in down regulation of EMT gene expression in C4-2 siAR cells [8].
