Translational Oncology, Genentech, Inc., South San Francisco, California.
Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
Clin Cancer Res. 2014 Dec 15;20(24):6324-35. doi: 10.1158/1078-0432.CCR-13-3336. Epub 2014 Oct 17.
The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3.
Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab. Serum and urinary levels of MMP-1 and MMP-10 were determined in healthy donors and patients with bladder cancer. The modulation of MMP-1 and MMP-10 by R3Mab in patients with bladder cancer was further evaluated in a phase I dose-escalation study.
MMP-1 and MMP-10 mRNA and protein were downmodulated by FGFR3 shRNA and R3Mab in bladder cancer cell lines. FGFR3 signaling promoted the expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. In bladder cancer xenograft models, R3Mab 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, both MMP-1 and pro-MMP-10 were elevated in the urine of patients with advanced bladder cancer. In a phase I dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in patients with bladder cancer.
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 R3Mab in patients with bladder cancer.
本研究旨在鉴定针对膀胱癌的 FGFR3 靶向治疗的非侵入性药效动力学生物标志物，以促进针对 FGFR3 的实验性药物的临床开发。
在临床前模型中，通过转录谱分析和生化分析相结合，确定了潜在的 FGFR3 靶向治疗的可溶性药效动力学生物标志物。选择两种基质金属蛋白酶（MMP），MMP-1 和 MMP-10，用于进一步研究在接受特异性抗 FGFR3 单克隆抗体 R3Mab 治疗的人膀胱癌异种移植模型中。测定健康供体和膀胱癌患者的血清和尿液中 MMP-1 和 MMP-10 的水平。在一项 I 期剂量递增研究中，进一步评估了 R3Mab 对膀胱癌患者 MMP-1 和 MMP-10 的调节作用。
FGFR3 shRNA 和 R3Mab 在膀胱癌细胞系中下调 MMP-1 和 MMP-10 mRNA 和蛋白。FGFR3 信号通过 MEK 依赖性方式促进 MMP-1 和 pro-MMP-10 的表达和分泌。在膀胱癌异种移植模型中，R3Mab 显著阻断肿瘤进展，并降低肿瘤组织以及小鼠血清中人 MMP-1 和 pro-MMP-10 的蛋白水平。此外，晚期膀胱癌患者的尿液中 MMP-1 和 pro-MMP-10 均升高。在一项 I 期剂量递增试验中，R3Mab 给药导致膀胱癌患者尿液中 MMP-1 和 pro-MMP-10 水平的急性降低。
这些发现揭示了 FGFR3 在调节 MMP-1 和 pro-MMP-10 表达和分泌中的关键作用，并鉴定出尿液中的 MMP-1 和 pro-MMP-10 作为 R3Mab 治疗膀胱癌患者的潜在药效动力学生物标志物。
