11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration
File(s)
Author(s)
Type
Journal Article
Abstract
BACKGROUND. Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically relevant concentrations in patients with CRPC to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in patients with CRPC.
METHODS. Patients with metastatic CRPC (n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing.
RESULTS. 11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43%–79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%–89%) and testosterone by 68% (38%–79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes.
CONCLUSION. The potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC.
TRIAL REGISTRATION. Netherlands Trial Register: NL5625 (NTR5732).
FUNDING. Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).
METHODS. Patients with metastatic CRPC (n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing.
RESULTS. 11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43%–79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%–89%) and testosterone by 68% (38%–79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes.
CONCLUSION. The potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC.
TRIAL REGISTRATION. Netherlands Trial Register: NL5625 (NTR5732).
FUNDING. Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).
Date Issued
2021-06-08
Date Acceptance
2021-04-29
Citation
JCI Insight, 2021, 6 (11)
ISSN
2379-3708
Publisher
American Society for Clinical investigation
Journal / Book Title
JCI Insight
Volume
6
Issue
11
Copyright Statement
© 2021, Snaterse et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33974560
PII: 148507
Subjects
ABIRATERONE ACETATE
C19 STEROIDS
CYP17
ENZALUTAMIDE
EXPRESSION
GENES
INCREASED SURVIVAL
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
RESISTANCE
Science & Technology
TESTOSTERONE
TRIALS
Publication Status
Published
Coverage Spatial
United States
Article Number
e148507
Date Publish Online
2021-05-11