LuCaP Prostate Cancer Patient‐Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an­­d Serve as Models for Evaluating Cancer Therapeutics

BACKGROUND Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long‐term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of biology of this malignancy and to evaluate new agents that migh...

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Published in:The Prostate Vol. 77; no. 6; pp. 654 - 671
Main Authors: Nguyen, Holly M., Vessella, Robert L., Morrissey, Colm, Brown, Lisha G., Coleman, Ilsa M., Higano, Celestia S., Mostaghel, Elahe A., Zhang, Xiaotun, True, Lawrence D., Lam, Hung‐Ming, Roudier, Martine, Lange, Paul H., Nelson, Peter S., Corey, Eva
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01.05.2017
John Wiley and Sons Inc
Subjects:
Animals
bone response
Genetic Heterogeneity
Heterografts - pathology
Humans
Male
Mice
Mice, Nude
Mice, SCID
Original
patient‐derived xenografts
prostate cancer
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
response to castration
Tumor Burden - genetics
Xenograft Model Antitumor Assays - methods
prostate cancer
response to castration
bone response
patient-derived xenografts
ISSN:0270-4137, 1097-0045
Online Access:Get full text
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Summary:BACKGROUND Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long‐term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of biology of this malignancy and to evaluate new agents that might provide effective treatment. Our objective was to establish and characterize patient‐derived xenografts (PDXs) from advanced prostate cancer (PC) for investigation of biology and evaluation of new treatment modalities. METHODS Samples of advanced PC obtained from primary prostate cancer obtained at surgery or from metastases collected at time of death were implanted into immunocompromised mice to establish PDXs. Established PDXs were propagated in vivo. Genomic, transcriptomic, and STR profiles were generated. Responses to androgen deprivation and docetaxel in vivo were characterized. RESULTS We established multiple PDXs (LuCaP series), which represent the major genomic and phenotypic features of the disease in humans, including amplification of androgen receptor, PTEN deletion, TP53 deletion and mutation, RB1 loss, TMPRSS2‐ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss. The PDX models also exhibit variation in intra‐tumoral androgen levels. Our in vivo results show heterogeneity of response to androgen deprivation and docetaxel, standard therapies for advanced PC, similar to the responses of patients to these treatments. CONCLUSIONS The LuCaP PDX series reflects the diverse molecular composition of human castration‐resistant PC and allows for hypothesis‐driven cause‐and‐effect studies of mechanisms underlying treatment response and resistance. Prostate 77: 654–671, 2017. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.
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Current Institution of Martine Roudier is AstraZeneca, Pathology, Translational Oncology, Cambridge, UK.
Current institution of Xiaotun Zhang is Pathology, Mayo Clinic, Rochester, MI, USA.
Conflicts of interest: The authors declare no potential conflicts of interest.
Holly M. Nguyen and Robert L. Vessella are the co‐primary lead authors.
ISSN:0270-4137
1097-0045
DOI:10.1002/pros.23313