Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies
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Wolfgang Jäger1,2,*, Hui Xue3,*, Tetsutaro Hayashi1, Claudia Janssen1, Shannon Awrey1, Alexander W. Wyatt1, Shawn Anderson1, Igor Moskalev1, Anne Haegert1, Mohammed Alshalalfa4, Nicholas Erho4, Elai Davicioni4, Ladan Fazli1, Estelle Li1, Colin Collins1, Yuzhuo Wang1,3, Peter C. Black1
1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
2Department of Urology, Johannes Gutenberg University, Mainz, Germany
3Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, BC, Canada
4Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada
*These authors have contributed equally to this work
Peter C. Black, e-mail: [email protected]
Keywords: bladder cancer, muscle invasive bladder cancer, targeted therapy, patient-derived cancer xenografts, animal model
Received: February 10, 2015 Accepted: May 15, 2015 Published: May 27, 2015
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.
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