TY - JOUR

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

AU - Saeed, Khalid

AU - Rahkama, Vesa

AU - Eldfors, Samuli

AU - Bychkov, Dmitry

AU - Mpindi, John Patrick

AU - Yadav, Bhagwan

AU - Paavolainen, Lassi

AU - Aittokallio, Tero

AU - Heckman, Caroline

AU - Wennerberg, Krister

AU - Peehl, Donna M

AU - Horvath, Peter

AU - Mirtti, Tuomas

AU - Rannikko, Antti

AU - Kallioniemi, Olli

AU - Östling, Päivi

AU - Af Hällström, Taija M

N1 - Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

KW - Aniline Compounds/pharmacology

KW - Antineoplastic Agents/pharmacology

KW - Cellular Reprogramming Techniques

KW - Drug Screening Assays, Antitumor

KW - High-Throughput Screening Assays

KW - Humans

KW - Kallikreins/metabolism

KW - Keratin-18/metabolism

KW - Keratin-5/metabolism

KW - Male

KW - Organoplatinum Compounds/pharmacology

KW - Precision Medicine

KW - Prostate-Specific Antigen/metabolism

KW - Prostatic Neoplasms, Castration-Resistant/drug therapy

KW - Quinacrine/pharmacology

KW - Receptors, Androgen/metabolism

KW - Sulfonamides/pharmacology

KW - Tetrahydronaphthalenes/pharmacology

KW - Tretinoin/pharmacology

KW - Tumor Cells, Cultured/drug effects

U2 - 10.1016/j.eururo.2016.04.019

DO - 10.1016/j.eururo.2016.04.019

M3 - Journal article

C2 - 27160946

VL - 71

SP - 319

EP - 327

JO - European Urology (Italian Edition)

JF - European Urology (Italian Edition)

SN - 1828-6569

IS - 3

ER -