title: Comprehensive Drug Testing of Patient-derived Conditionally Reprogrammed Cells from Castration-resistant Prostate Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Khalid
authors.initials: K
authors.lastname: Saeed
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Vesa
authors.initials: V
authors.lastname: Rahkama
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Samuli
authors.initials: S
authors.lastname: Eldfors
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Bychkov
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: John Patrick
authors.initials: JP
authors.lastname: Mpindi
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Bhagwan
authors.initials: B
authors.lastname: Yadav
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Lassi
authors.initials: L
authors.lastname: Paavolainen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Heckman
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Krister
authors.initials: K
authors.lastname: Wennerberg
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Synthetic and System Biology Unit, Biological Research Center, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvath
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.affiliation: Department of Urology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Rannikko
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Östling
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland. Electronic address: taija.afhallstrom@helsinki.fi.
authors.forename: Taija M
authors.initials: TM
authors.lastname: Af Hällström
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D000067470:Cellular Reprogramming Techniques; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D053538:Keratin-18 / Q000378:metabolism; D053555:Keratin-5 / Q000378:metabolism; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D057285:Precision Medicine; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: C410798:AR protein, human; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D053538:Keratin-18; D053555:Keratin-5; D009944:Organoplatinum Compounds; D011944:Receptors, Androgen; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D000077150:Oxaliplatin; D014212:Tretinoin; D000077610:Bexarotene; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D011796:Quinacrine; C528561:navitoclax
keywords: Castration-resistant prostate cancer; Drug sensitivity testing; Navitoclax; Patient-derived cultures; Reprogrammed cells