Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure
| Autor: | Jianbo Li, Nima Sharifi, S. Taylor, Mohammad Alyamani, Ravi A. Madan, Mona Patel, Brian I. Rini, James L. Gulley, M. Berk, Christopher G. Przybycin, Eric A. Klein, Jorge A. Garcia, Edwin M. Posadas, Fumihiko Nakamura |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Kidney 03 medical and health sciences Prostate cancer chemistry.chemical_compound 0302 clinical medicine Tandem Mass Spectrometry Internal medicine medicine Enzalutamide Humans Glucocorticoids Prostvac business.industry Apalutamide Prostatic Neoplasms Hematology medicine.disease Androgen receptor Prostatic Neoplasms Castration-Resistant 030104 developmental biology Endocrinology Oncology chemistry Receptors Androgen 030220 oncology & carcinogenesis Hormonal therapy Cortisone business Glucocorticoid medicine.drug Chromatography Liquid |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 31(3) |
| ISSN: | 1569-8041 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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