FKBP5 mRNA Expression is a Biomarker for GR Antagonism

Bali, U., Phillips, T., Hunt, H., and Unitt, J.

J Clin Endocrinol Metab. 2016 Nov;101(11):4305-4312

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: To develop a qPCR 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

Methods: Briefly: blood samples were acquired from a phase I study in which healthy human subjects were administered either (a) a single dose of the GR agonist prednisone with and without
co-administration of a single oral dose of mifepristone or CORT125134 or (b) multiple daily doses of CORT125134 over 14 days with co-administration of prednisone with the final dose. FKBP5
mRNA levels were analyzed by qPCR in blood samples collected at selected time points.

Setting: Quotient Clinical, Nottingham, UK.

Results: Oral administration of the glucocorticoid prednisone to healthy human subjects resulted in a time-dependent increase of FKBP5 mRNA to peak levels of ~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.