title: Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer.
abstract: Activating mutations of fibroblast growth factor receptor-3 (FGFR3) have been described in approximately 75% of low-grade papillary bladder tumors. In muscle-invasive disease, FGFR3 mutations are found in 20% of tumors, but overexpression of FGFR3 is observed in about half of cases. Therefore, FGFR3 is a particularly promising target for therapy in bladder cancer. Up to now, most drugs tested for inhibition of FGFR3 have been small molecule, multityrosine kinase inhibitors. More recently, a specific inhibitory monoclonal antibody targeting FGFR3 (R3Mab) has been described and tested preclinically. In this study, we have evaluated mutation and expression status of FGFR3 in 19 urothelial cancer cell lines and a cohort of 170 American patients with bladder cancer. We have shown inhibitory activity of R3Mab on tumor growth and corresponding cell signaling in three different orthotopic xenografts of bladder cancer. Our results provide the preclinical proof of principle necessary to translate FGFR3 inhibition with R3Mab into clinical trials in patients with bladder cancer.
authors: Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
authors: Kilian M
authors: KM
authors: Gust
authors: David J
authors: DJ
authors: McConkey
authors: Shannon
authors: S
authors: Awrey
authors: Paul K
authors: PK
authors: Hegarty
authors: Jing
authors: J
authors: Qing
authors: Jolanta
authors: J
authors: Bondaruk
authors: Avi
authors: A
authors: Ashkenazi
authors: Bogdan
authors: B
authors: Czerniak
authors: Colin P
authors: CP
authors: Dinney
authors: Peter C
authors: PC
authors: Black
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051498:Receptor, Fibroblast Growth Factor, Type 3
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