Data from Targeting Fibroblast Growth Factor Receptor Signaling Inhibits Prostate Cancer Progression

<div>Abstract<p><b>Purpose:</b> Extensive correlative studies in human prostate cancer as well as studies <i>in vitro</i> and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1–3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have <i>in vitro</i> activities consistent with inhibition of tumor progression and will inhibit tumor progression <i>in vivo</i>.</p><p><b>Experimental Design:</b> Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation <i>in vitro</i> was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression <i>in vivo</i> was evaluated using a VCaP xenograft model.</p><p><b>Results:</b> AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable <i>in vivo</i> concentration. This results in marked inhibition of extracellular signal–regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment <i>in vivo</i> completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors.</p><p><b>Conclusions:</b> Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer. <i>Clin Cancer Res; 18(14); 3880–8. ©2012 AACR</i>.</p></div>