Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

Chromatography, Liquid Glucocorticoids Humans Kidney Male Prostatic Neoplasms Prostatic Neoplasms, Castration-Resistant / drug therapy Receptors, Androgen / genetics Tandem Mass Spectrometry
androgens apalutamide enzalutamide glucocorticoids hormonal therapy prostate cancer

Journal

Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735

Informations de publication

Date de publication:
03 2020
Historique:
received: 06 10 2019
revised: 23 11 2019
accepted: 10 12 2019
pubmed: 15 2 2020
medline: 7 1 2021
entrez: 15 2 2020
Statut: ppublish

Résumé

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Sections du résumé

BACKGROUND
Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences.
PATIENTS AND METHODS
Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median.
RESULTS
Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed.
CONCLUSION
Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Identifiants

DOI: 10.1016/j.annonc.2019.12.002 PMID: 32057540 PMC: PMC7460727
pubmed: 32057540
pii: S0923-7534(19)53225-2
doi: 10.1016/j.annonc.2019.12.002
pmc: PMC7460727
mid: NIHMS1618418
pii:
doi:

Substances chimiques

Glucocorticoids 0
Receptors, Androgen 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

369-376

Subventions

Organisme : NCI NIH HHS
ID : R01 CA172382
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190289
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236780
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure The authors have declared no conflicts of interest.

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Auteurs

M Alyamani (M)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

J Li (J)

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

M Patel (M)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

S Taylor (S)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

F Nakamura (F)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

M Berk (M)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

C Przybycin (C)

Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, USA.

E M Posadas (EM)

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.

R A Madan (RA)

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA.

J L Gulley (JL)

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, USA.

B Rini (B)

Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA.

J A Garcia (JA)

Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA.

E A Klein (EA)

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA.

N Sharifi (N)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA; Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, USA; Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA. Electronic address: sharifn@ccf.org.

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Classifications MeSH

questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Chromatographie › Chromatographie en phase liquide › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hormones, substituts d'hormones et antagonistes d'hormones › Hormones › Glucocorticoïdes › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Tumeurs prostatiques résistantes à la castration › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs aux androgènes › Deep androgen receptor suppression in prostate...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Spectrométrie de masse › Spectrométrie de masse en tandem › Deep androgen receptor suppression in prostate...