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

Aditya Dutta, Sukanya Panja, Renu K. Virk, Jaime Yeji Kim, Roseann Zott, Serge Cremers, David M. Golombos, Deli Liu, Juan Miguel Mosquera, Elahe A. Mostaghel, Christopher E. Barbieri, Antonina Mitrofanova, Cory Abate-Shen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background 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. Objective To identify molecular features predictive of patient response to 5-ARIs. Design, setting, and participants 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. Intervention Finasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively. Outcome measurements and statistical analysis Endpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses. Results and limitations 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. Conclusions 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. Patient summary 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. This co-clinical study implicates NKX3.1 status as a predictor of response to 5α-reductase inhibitors, and suggests that specific molecular features, including NKX3.1 expression, may help to identify prostate cancer patients most likely to benefit from 5α-reductase inhibitor intervention during active surveillance.

Original languageEnglish (US)
Pages (from-to)499-506
Number of pages8
JournalEuropean Urology
Volume72
Issue number4
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Urology

Keywords

  • 5α-Reductase inhibitors
  • Active surveillance
  • Chemoprevention
  • Dutasteride
  • Finasteride
  • NKX3.1
  • Precision cancer prevention
  • Prostate cancer

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this