TY - JOUR
T1 - Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response
AU - Shafi, Ayesha A.
AU - Schiewer, Matthew J.
AU - de Leeuw, Renée
AU - Dylgjeri, Emanuela
AU - McCue, Peter A.
AU - Shah, Neelima
AU - Gomella, Leonard G.
AU - Lallas, Costas D.
AU - Trabulsi, Edouard J.
AU - Centenera, Margaret M.
AU - Hickey, Theresa E.
AU - Butler, Lisa M.
AU - Raj, Ganesh V.
AU - Tilley, Wayne D.
AU - Cukierman, Edna
AU - Knudsen, Karen E.
N1 - Funding Information:
Funding/Support and role of the sponsor : This work was supported by Prostate Cancer Foundation Young Investigator Awards (Ayesha A. Shafi 2017, Matthew J. Schiewer 2013, Renée de Leeuw 2016); NIH/NCI grants to Karen E. Knudsen (R01 CA159945, R01 CA176401, R01 CA182569, R01 CA217329); an NIH/NCI grant to Edna Cukierman (R01 CA113451); core grant CA06927 in support of the Fox Chase Core Facilities (Talbot Library, Bio-Sample Repository, and Cell Imaging); funds from the Commonwealth of Pennsylvania and Mrs. Concetta Greenberg on behalf of Dr. Martin Greenberg; an Australian Research Council Future Fellowship to Lisa M. Butler (ST130101004); a Prostate Cancer Foundation of Australia grant to Margaret M. Centenera (YIG0412); a Movember Foundation grant to Lisa M. Butler and Wayne D. Tilley (MRTA3); and a Cancer Australia grant to Margaret M. Centenera, Lisa M. Butler, and Wayne D. Tilley (1085471). The sponsors played a role in the design and conduct of the study; data collection, management, analysis, and interpretation; and preparation, review, and approval of the manuscript.
Publisher Copyright:
© 2018 European Association of Urology
PY - 2018/9
Y1 - 2018/9
N2 - Background: Androgen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response. Objective: To leverage the ex vivo culture method termed patient-derived explant (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis. Design, setting, and participants: Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response. Outcome measurements and statistical analysis: The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices). Results and limitations: PDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics. Conclusions: The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes. Patient summary: In this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer. The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices.
AB - Background: Androgen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response. Objective: To leverage the ex vivo culture method termed patient-derived explant (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis. Design, setting, and participants: Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response. Outcome measurements and statistical analysis: The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices). Results and limitations: PDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics. Conclusions: The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes. Patient summary: In this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer. The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices.
KW - Androgen receptor
KW - Ex vivo
KW - Prostate cancer
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85055864115&partnerID=8YFLogxK
U2 - 10.1016/j.euo.2018.04.019
DO - 10.1016/j.euo.2018.04.019
M3 - Article
C2 - 30467556
AN - SCOPUS:85055864115
SN - 2588-9311
VL - 1
SP - 325
EP - 337
JO - European Urology Oncology
JF - European Urology Oncology
IS - 4
ER -