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.

A Place for Precision Medicine in Bladder Cancer: Targeting the Fgfrs

“…Patient-derived xenografts (PDXs) or tumor organoids may be superior models. A REviEW di Martino, Tomlinson, Williams & Knowles future science group recent study described several PDXs derived from MIBC, one of which contained an FGFR3 mutation and showed good response to the FGFR3specific antibody R3Mab [154]. To date no organoid models of bladder cancer have been reported.…”

ALDH1A1 in patient‐derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression

“…Moreover, these PDCs and the PDC‐derived xenografts maintained similar pathohistological characteristics to the source tumors. We therefore suggest that the models generated here reflect clinical presentation in the original cancer patients . Recently, several lines of evidence have suggested that 3D culture systems may more adequately replicate the cellular microenvironment than conventional 2D culture .…”

“…We therefore suggest that the models generated here reflect clinical presentation in the original cancer patients. 12,13,23 Recently, several lines of evidence have suggested that 3D culture systems may more adequately replicate the cellular microenvironment than conventional 2D culture. 24 Therefore, the bladder cancer PDCs generated in the present study would facilitate drug discovery and therapeutic development for bladder cancer.…”

Spontaneous tumors in pets are an excellent translational model for human cancers

“…In contrast, translational studies using mice increasingly make use of human tumor tissue taken directly from the patient, without in vitro clonal selection, providing a robust snapshot of the tumor taken at the precise time therapy is to be applied. 16 This approach therefore retains the genetic uniqueness of individual patient tumors, representing the culmination of the tortuous genetic path the tumor has taken to presentation as a clinical problem.…”