title: Co-clinical Analysis of a Genetically Engineered Mouse Model and Human Prostate Cancer Reveals Significance of NKX3.1 Expression for Response to 5α-reductase Inhibition.
abstract: Although men on active surveillance for prostate cancer (PCa) may benefit from intervention with 5α-reductase inhibitors (5-ARIs), it has not been resolved whether 5-ARIs are effective for delaying disease progression and, if so, whether specific patients are more likely to benefit.
  
  
  
  To identify molecular features predictive of patient response to 5-ARIs.
  
  
  
  Nkx3.1 mutant mice, a model of early-stage PCa, were treated with the 5-ARI finasteride, and histopathological and molecular analyses were performed. Cross-species computational analyses were used to compare expression profiles for treated mice with those of patients who had received 5-ARIs before prostatectomy.
  
  
  
  Finasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively.
  
  
  
  Endpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses.
  
  
  
  Finasteride treatment of Nkx3.1 mutant mice resulted in a significant reduction in prostatic intraepithelial neoplasia (PIN), as evident from histopathological and expression profiling analyses. Cross-species computational analysis comparing finasteride-treated mice with two independent 5-ARI-treated patient cohorts showed that reduced NKX3.1 expression is predictive of response to 5-ARI. A limitation of the study is that these retrospective human cohorts have relatively few patients with limited clinical outcome data. Future prospective clinical trials are needed to validate whether stratifying patients on the basis of NKX3.1 expression improves the benefit of 5-ARIs during active surveillance.
  
  
  
  This co-clinical study implicates NKX3.1 status as a predictor of response to 5-ARIs, and suggests that molecular features, including NKX3.1 expression, may help to identify PCa patients most likely to benefit from 5-ARIs during active surveillance.
  
  
  
  The aim of precision cancer prevention is to tailor interventions on the basis of individualized patient characteristics. We propose that patients with low NKX3.1 expression are optimal candidates for intervention with 5α-reductase inhibitors as an adjunct to active surveillance.
authors.affiliation: Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Panja
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, NY, USA.
authors.forename: Renu K
authors.initials: RK
authors.lastname: Virk
authors.affiliation: Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Jaime Yeji
authors.initials: JY
authors.lastname: Kim
authors.affiliation: The Irving Institute for Clinical and Translational Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Roseann
authors.initials: R
authors.lastname: Zott
authors.affiliation: Departments of Pathology & Cell Biology and Medicine, The Irving Institute for Clinical and Translational Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Department of Urology, Weill Cornell Medicine, New York, NY, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Golombos
authors.affiliation: Department of Urology, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Deli
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.affiliation: Department of Urology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Barbieri
authors.affiliation: Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA. Electronic address: antonina.mitrofanova@rutgers.edu.
authors.forename: Antonina
authors.initials: A
authors.lastname: Mitrofanova
authors.affiliation: Departments of Urology, Medicine, Pathology & Cell Biology, and Systems Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA. Electronic address: cabateshen@columbia.edu.
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D000066491:Clinical Decision-Making; D004252:DNA Mutational Analysis; D000068538:Dutasteride / Q000009:adverse effects / Q000627:therapeutic use*; D018120:Finasteride / Q000009:adverse effects / Q000627:therapeutic use*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011468:Prostatectomy; D019048:Prostatic Intraepithelial Neoplasia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D058891:5-alpha Reductase Inhibitors; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D018120:Finasteride; D000068538:Dutasteride
keywords: 5α-Reductase inhibitors; Active surveillance; Chemoprevention; Dutasteride; Finasteride; NKX3.1; Precision cancer prevention; Prostate cancer