title: Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies.
abstract: Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC). One PDX harbouring an FGFR3 mutation was treated with an inhibitory monoclonal antibody targeting FGFR3. Five PDX were successfully established. Tumor doubling time ranged from 5 to 11 days. Array CGH revealed shared chromosomal aberrations in the patient tumors and PDX. Gene expression microarray and IHC confirmed that PDXs maintain similar patterns to the parental tumors. Tumor growth in the PDX with an FGFR3 mutation was inhibited by the FGFR3 inhibitor. PDXs recapitulate the tumor biology of the patients' primary tumors from which they are derived. Investigations related to tumor biology and drug testing in these models are therefore more likely to be relevant to the disease state in patients. They represent a valuable tool for developing precision therapy in MIBC.
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.|Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Janssen
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Awrey
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Moskalev
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.affiliation: Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Estelle
authors.initials: E
authors.lastname: Li
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.|Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000368:Aged; D000818:Animals; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: animal model; bladder cancer; muscle invasive bladder cancer; patient-derived cancer xenografts; targeted therapy