Abstract
Abstract Aberrant activation of fibroblast growth factor receptor 3 (FGFR3) via overexpression or mutation occurs frequently in bladder cancer, and experimental therapeutic agents have entered into clinical trials to evaluate the potential activity of FGFR3-targeted therapy in this disease. However, a convenient accessible biomarker indicative of targeted pathway modulation in vivo drug activity is urgently needed. Through transcriptional profiling of bladder carcinoma cells expressing inducible FGFR3 short hairpin RNAs, we identified two matrix metalloproteinases (MMPs), MMP-1 and MMP-10, as potential downstream targets of FGFR3. We found that FGFR3 signaling promotes expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. FGFR3 inhibition by an investigational anti-FGFR3 human monoclonal antibody, R3Mab, in bladder cancer xenograft models substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, we detected elevated levels of both MMP-1 and pro-MMP-10 in the urine of patients with advanced bladder cancer. In a phase 1 dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in bladder cancer patients. Together, these findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for FGFR3-targeted therapy in bladder cancer. Citation Format: Benjamin C. Lin, Xiangnan Du, Qian-Rena Wang, Hao Li, Ellen Ingalla, Janet Tien, Isabelle Rooney, Avi Ashkenazi, Elicia Penuel, Jing Qing. MMP-1 and pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2014-3690
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