Sammanfattning

Background

Technology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa.

Objective

We established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs.

Design, setting, and participants

CRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling.

Outcome measurements and statistical analysis

The phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language.

Results and limitations

We generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids.

Conclusions

Comprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC.

Patient summary

We describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.
Originalspråkengelska
TidskriftEuropean Urology
Volym71
Utgåva3
Sidor (från-till)319-327
Antal sidor9
ISSN0302-2838
DOI
StatusPublicerad - 2017
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3126 Kirurgi, anestesiologi, intensivvård, radiologi

Citera det här

@article{10a135581204415cb36c8c6fa24a7e61,
title = "Comprehensive Drug Testing of Patient-derived Conditionally Reprogrammed Cells from Castration-resistant Prostate Cancer",
abstract = "BackgroundTechnology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa.ObjectiveWe established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs.Design, setting, and participantsCRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling.Outcome measurements and statistical analysisThe phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language.Results and limitationsWe generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids.ConclusionsComprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC.Patient summaryWe describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.",
keywords = "3126 Surgery, anesthesiology, intensive care, radiology",
author = "Khalid Saeed and Vesa-Pekka Rahkama and Samuli Eldfors and Dmitrii Bychkov and Mpindi, {John Patrick} and Bhagwan Yadav and Paavolainen, {Lassi Olavi} and Aittokallio, {Tero Antero} and Heckman, {Caroline Akemi} and Wennerberg, {Johan Krister} and Rannikko, {Antti Sakari} and Peter Horvath and Mirtti, {Tuomas Kristian} and D Peehl and Olli-Pekka Kallioniemi and {\"O}stling, {P{\"a}ivi Kristiina} and {af H{\"a}llstr{\"o}m}, {Taija Maria}",
year = "2017",
doi = "10.1016/j.eururo.2016.04.019",
language = "English",
volume = "71",
pages = "319--327",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier Scientific Publ. Co",
number = "3",

}

TY - JOUR

T1 - Comprehensive Drug Testing of Patient-derived Conditionally Reprogrammed Cells from Castration-resistant Prostate Cancer

AU - Saeed, Khalid

AU - Rahkama, Vesa-Pekka

AU - Eldfors, Samuli

AU - Bychkov, Dmitrii

AU - Mpindi, John Patrick

AU - Yadav, Bhagwan

AU - Paavolainen, Lassi Olavi

AU - Aittokallio, Tero Antero

AU - Heckman, Caroline Akemi

AU - Wennerberg, Johan Krister

AU - Rannikko, Antti Sakari

AU - Horvath, Peter

AU - Mirtti, Tuomas Kristian

AU - Peehl, D

AU - Kallioniemi, Olli-Pekka

AU - Östling, Päivi Kristiina

AU - af Hällström, Taija Maria

PY - 2017

Y1 - 2017

N2 - BackgroundTechnology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa.ObjectiveWe established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs.Design, setting, and participantsCRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling.Outcome measurements and statistical analysisThe phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language.Results and limitationsWe generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids.ConclusionsComprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC.Patient summaryWe describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.

AB - BackgroundTechnology development to enable the culture of human prostate cancer (PCa) progenitor cells is required for the identification of new, potentially curative therapies for PCa.ObjectiveWe established and characterized patient-derived conditionally reprogrammed cells (CRCs) to assess their biological properties and to apply these to test the efficacies of drugs.Design, setting, and participantsCRCs were established from seven patient samples with disease ranging from primary PCa to advanced castration-resistant PCa (CRPC). The CRCs were characterized by genomic, transcriptomic, protein expression, and drug profiling.Outcome measurements and statistical analysisThe phenotypic quantification of the CRCs was done based on immunostaining followed by image analysis with Advanced Cell Classifier using Random Forest supervised machine learning. Copy number aberrations (CNAs) were called from whole-exome sequencing and transcriptomics using in-house pipelines. Dose-response measurements were used to generate multiparameter drug sensitivity scores using R-statistical language.Results and limitationsWe generated six benign CRC cultures which all had an androgen receptor-negative, basal/transit-amplifying phenotype with few CNAs. In three-dimensional cell culture, these cells could re-express the androgen receptor. The CRCs from a CRPC patient (HUB.5) displayed multiple CNAs, many of which were shared with the parental tumor. We carried out high-throughput drug-response studies with 306 emerging and clinical cancer drugs. Using the benign CRCs as controls, we identified the Bcl-2 family inhibitor navitoclax as the most potent cancer-specific drug for the CRCs from a CRPC patient. Other drug efficacies included taxanes, mepacrine, and retinoids.ConclusionsComprehensive cancer pharmacopeia-wide drug testing of CRCs from a CRPC patient highlighted both known and novel drug sensitivities in PCa, including navitoclax, which is currently being tested in clinical trials of CRPC.Patient summaryWe describe an approach to generate patient-derived cancer cells from advanced prostate cancer and apply such cells to discover drugs that could be applied in clinical trials for castration-resistant prostate cancer.

KW - 3126 Surgery, anesthesiology, intensive care, radiology

UR - http://www.sciencedirect.com/science/article/pii/S030228381630080X

U2 - 10.1016/j.eururo.2016.04.019

DO - 10.1016/j.eururo.2016.04.019

M3 - Article

VL - 71

SP - 319

EP - 327

JO - European Urology

JF - European Urology

SN - 0302-2838

IS - 3

ER -