Dataset Information

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:

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.

SUBMITTER: Dutta A

PROVIDER: S-EPMC5600823 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Dutta Aditya A Panja Sukanya S Virk Renu K RK Kim Jaime Yeji JY Zott Roseann R Cremers Serge S Golombos David M DM Liu Deli D Mosquera Juan Miguel JM Mostaghel Elahe A EA Barbieri Christopher E CE Mitrofanova Antonina A Abate-Shen Cory C

European urology 20170404 4

<h4>Background</h4>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.<h4>Objective</h4>To identify molecular features predictive of patient response to 5-ARIs.<h4>Design, setting, and participants</h4>Nkx3.1 mutant mice, a model of early-stage PCa, were treated with ...[more]

PMID: 28385453

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Project description:ImportanceThere is evidence that 5α-reductase inhibitors (5-ARIs), a standard treatment of benign prostate hyperplasia, are associated with a decrease in the incidence of prostate cancer (PCa). However, studies to date have had conflicting results regarding the association with prostate cancer mortality (PCM).ObjectiveTo evaluate the association of treatment with 5-ARIs with PCM in men without a prior diagnosis of PCa.Design, setting, and participantsThis population-based cohort study was conducted in Stockholm, Sweden, between January 1, 2007, and December 31, 2018, and included 429 977 men with a prostate-specific antigen (PSA) test within the study period. Study entry was set to 1 year after the first PSA test. Data were analyzed from September 2021 to December 2021.ExposuresAfter their initial PSA test, men with 2 or more newly dispensed prescriptions of 5-ARI, finasteride, or dutasteride were considered 5-ARI users (n = 26 190).Main outcomes and measuresPrimary outcome was PCM. Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs for all-cause mortality and PCM.ResultsThe study cohort included 349 152 men. The median (IQR) age for those with 2 or more filled prescriptions of 5-ARI was 66 (61-73) years and 57 (50-64) years for those without. The median follow-up time was 8.2 (IQR, 4.9-10) years with 2 257 619 person-years for the unexposed group and 124 008 person-years for the exposed group. The median exposure to treatment with 5-ARI was 4.5 (IQR, 2.1-7.4) years. During follow-up, 35 767 men (8.3%) died, with 852 deaths associated with PCa. The adjusted multivariable survival analysis showed a lower risk of PCM in the 5-ARI group with longer exposure times (0.1-2.0 years: adjusted HR, 0.89; 95% CI, 0.64-1.25; >8 years: adjusted HR, 0.44; 95% CI, 0.27-0.74). No statistically significant differences were seen in all-cause mortality between the exposed and unexposed group. Men treated with 5-ARIs underwent more PSA tests and biopsies per year than the unexposed group (median of 0.63 vs 0.33 and 0.22 vs 0.12, respectively).Conclusions and relevanceThe results of this cohort study suggest that there was no association between treatment with 5-ARI and increased PCM in a large population-based cohort of men without a previous PCa diagnosis. Additionally, a time-dependent association was seen with decreased risk of PCM with longer 5-ARI treatment. Further research is needed to determine whether the differences are because of intrinsic drug effects or PCa testing differences.

Project description:A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.

Project description:BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

Dataset Information

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.

Background

Objective

Design, setting, and participants

Intervention

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Publications

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.

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