title: MMP-1 and Pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Xiangnan
authors.initials: X
authors.lastname: Du
authors.affiliation: Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lin
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Qian-Rena
authors.initials: QR
authors.lastname: Wang
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ingalla
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Janet
authors.initials: J
authors.lastname: Tien
authors.affiliation: Oncology Clinical Science ECD, Genentech, Inc., South San Francisco, California.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rooney
authors.affiliation: Research Oncology, Genentech, Inc., South San Francisco, California.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.affiliation: Oncology Biomarker Development, Genentech, Inc., South San Francisco, California. epenuel@gene.com jqing@gene.com.
authors.forename: Elicia
authors.initials: E
authors.lastname: Penuel
authors.affiliation: Translational Oncology, Genentech, Inc., South San Francisco, California. epenuel@gene.com jqing@gene.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Qing
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000652:urine; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D004195:Disease Models, Animal; D004792:Enzyme Precursors; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000652:urine*; D053506:Matrix Metalloproteinase 10 / Q000235:genetics / Q000652:urine*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000652:urine*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015415:Biomarkers; D004792:Enzyme Precursors; D047428:Protein Kinase Inhibitors; D051498:Receptor, Fibroblast Growth Factor, Type 3; D053506:Matrix Metalloproteinase 10; D020781:Matrix Metalloproteinase 1