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.
Highlights
INTRODUCTION & OBJECTIVESAn estimated 74, 690 incident cases and 15, 580 deaths from bladder cancer are expected to occur in the United States in 2014
Patient tumor and PDX were processed for analysis of copy number variations by Array comparative genomic hybridization (aCGH), gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC)
Response to systemic chemotherapy is rarely durable in these patients and most will succumb to their disease
Summary
An estimated 74, 690 incident cases and 15, 580 deaths from bladder cancer are expected to occur in the United States in 2014. This will make it the fourth most common cancer in men and the twelfth most common cancer in women, which is representative of other industrialized countries [1]. Three quarters of these patients have non-muscle invasive tumors [2], which have a high disposition for recurrence after curative treatment, and a subset is at high risk for progression to invasive disease [3]. The remaining quarter of patients present with muscle invasive bladder cancer (MIBC). While targeted therapy has revolutionized the treatment of many cancers [5] no significant breakthroughs have been made for decades to enhance the systemic therapy of MIBC [6]
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