FKBP5 mRNA Expression Is a Biomarker for GR Antagonism
Context: Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitorin...
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Published in | The journal of clinical endocrinology and metabolism Vol. 101; no. 11; pp. 4305 - 4312 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
Endocrine Society
01.11.2016
Copyright by The Endocrine Society |
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Abstract | Context:
Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushing's syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models.
Objective:
The objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects.
Methods:
Briefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points.
Setting:
The study was conducted at Quotient Clinical (Nottingham, United Kingdom).
Results:
Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels.
Conclusions:
The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism.
In a human phase I study, mifepristone and the selective GR antagonist CORT125134 were shown to inhibit glucocorticoid-stimulated whole blood levels of FKBP5 mRNA, measured using real-time qPCR. |
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AbstractList | CONTEXT:Endogenous Cushingʼs syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushingʼs syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushingʼs syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models.
OBJECTIVE:The objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects.
METHODS:Briefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points.
SETTING:The study was conducted at Quotient Clinical (Nottingham, United Kingdom).
RESULTS:Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels.
CONCLUSIONS:The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism. CONTEXTEndogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushing's syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models.OBJECTIVEThe objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects.METHODSBriefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points.SETTINGThe study was conducted at Quotient Clinical (Nottingham, United Kingdom).RESULTSOral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels.CONCLUSIONSThe inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism. Context: Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushing's syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models. Objective: The objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects. Methods: Briefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points. Setting: The study was conducted at Quotient Clinical (Nottingham, United Kingdom). Results: Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels. Conclusions: The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism. In a human phase I study, mifepristone and the selective GR antagonist CORT125134 were shown to inhibit glucocorticoid-stimulated whole blood levels of FKBP5 mRNA, measured using real-time qPCR. Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for the treatment of Cushing's syndrome. Currently there is an unmet clinical need for a direct biochemical method for monitoring the immediate effectiveness of mifepristone in patients with Cushing's syndrome. The glucocorticoid induction of FK506-binding protein 5 (FKBP5) expression is rapid and has been shown to be attenuated by GR antagonists in a range of in vitro and in vivo models. The objective of the study was to develop a quantitative PCR assay for FKBP5 mRNA expression in blood and apply it to measure the inhibition of glucocorticoid-induced FKBP5 expression by GR antagonists in healthy human subjects. Briefly, blood samples were acquired from a phase I study in which healthy human subjects were administered either a single dose of the GR agonist prednisone with and without coadministration of a single oral dose of mifepristone or glucocorticoid receptor antagonist (CORT125134) or multiple daily doses of CORT125134 over 14 days with coadministration of prednisone with the final dose. FKBP5 mRNA levels were analyzed by quantitative PCR in blood samples collected at selected time points. The study was conducted at Quotient Clinical (Nottingham, United Kingdom). Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of approximately 12-fold compared with unstimulated levels within 4 hours of steroid administration, followed by a reduction to baseline levels within 24 hours. Furthermore, oral administration of mifepristone or the selective GR antagonist CORT125134 had the desired effect of inhibiting prednisone-mediated activation of GR as seen by a reduction of FKBP5 mRNA levels. The inhibition of FKBP5 mRNA expression by a selective GR antagonist is a potential clinical biomarker of GR antagonism. |
Author | Unitt, John Phillips, Tim Bali, Utsav Hunt, Hazel |
AuthorAffiliation | Bioscience Department (U.B., T.P., J.U.), Sygnature Discovery Ltd, BioCity, Nottingham NG1 1GF, United Kingdom; and Corcept Therapeutics (H.H.), Menlo Park, California 94025 |
AuthorAffiliation_xml | – name: Bioscience Department (U.B., T.P., J.U.), Sygnature Discovery Ltd, BioCity, Nottingham NG1 1GF, United Kingdom; and Corcept Therapeutics (H.H.), Menlo Park, California 94025 |
Author_xml | – sequence: 1 givenname: Utsav surname: Bali fullname: Bali, Utsav email: u.bali@sygnaturediscovery.com – sequence: 2 givenname: Tim surname: Phillips fullname: Phillips, Tim – sequence: 3 givenname: Hazel surname: Hunt fullname: Hunt, Hazel – sequence: 4 givenname: John surname: Unitt fullname: Unitt, John |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27459525$$D View this record in MEDLINE/PubMed |
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Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is... CONTEXT:Endogenous Cushingʼs syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is... Endogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved for... CONTEXTEndogenous Cushing's syndrome is caused by chronically elevated levels of cortisol. Mifepristone, a glucocorticoid receptor (GR) antagonist, is approved... |
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SubjectTerms | Adult Animals Biological Assay Biomarkers - blood Glucocorticoids - administration & dosage Glucocorticoids - pharmacology Hormone Antagonists - administration & dosage Hormone Antagonists - pharmacology Humans Male Middle Aged Mifepristone - administration & dosage Mifepristone - pharmacology Polymerase Chain Reaction Prednisone - administration & dosage Prednisone - pharmacology Rats Rats, Sprague-Dawley Receptors, Glucocorticoid - antagonists & inhibitors RNA, Messenger - blood RNA, Messenger - drug effects Tacrolimus Binding Proteins - blood Tacrolimus Binding Proteins - drug effects Young Adult |
Title | FKBP5 mRNA Expression Is a Biomarker for GR Antagonism |
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