LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d 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 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.
Department of Urology, University of Washington, Seattle, Washington.
Holly M
HM
Nguyen
Department of Urology, University of Washington, Seattle, Washington.|Puget Sound Veteran Administration, Seattle, Washington.
Robert L
RL
Vessella
Department of Urology, University of Washington, Seattle, Washington.
Colm
C
Morrissey
Department of Urology, University of Washington, Seattle, Washington.
Lisha G
LG
Brown
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Ilsa M
IM
Coleman
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Division of Oncology, Department of Medicine, University of Washington, Seattle, Washington.
Celestia S
CS
Higano
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Elahe A
EA
Mostaghel
Department of Urology, University of Washington, Seattle, Washington.
Xiaotun
X
Zhang
Department of Pathology, University of Washington, Seattle, Washington.
Lawrence D
LD
True
Department of Urology, University of Washington, Seattle, Washington.
Hung-Ming
HM
Lam
Department of Urology, University of Washington, Seattle, Washington.
Martine
M
Roudier
Department of Urology, University of Washington, Seattle, Washington.
Paul H
PH
Lange
Department of Urology, University of Washington, Seattle, Washington.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Pathology, University of Washington, Seattle, Washington.
Peter S
PS
Nelson
Department of Urology, University of Washington, Seattle, Washington.
Eva
E
Corey
D000818:Animals; D018740:Genetic Heterogeneity; D064593:Heterografts / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology*; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
bone response; patient-derived xenografts; prostate cancer; response to castration