FKBP5 Protein May Be Cortisol Activity Biomarker

Measuring the levels of the RNA molecule that provides instructions to make a protein called FKBP5 could be useful for assessing cortisol activity in people with Cushing’s disease, a new study indicates.

The study, “Evaluation of FKBP5 as a cortisol activity biomarker in patients with ACTH-dependent Cushing syndrome,” was published in the Journal of Clinical & Translational Endocrinology. It was sponsored by Corcept Therapeutics, the company that markets Korlym (mifepristone), an approved medication for controlling blood sugar levels in patients with Cushing’s who also have type 2 diabetes or glucose intolerance.

Cushing’s syndrome comprises a group of disorders characterized by abnormally high levels of the stress hormone cortisol. Cushing’s disease is a specific form of the syndrome caused by a tumor in the brain’s pituitary gland.

Cortisol has a variety of effects on the body, which the hormone enacts by binding to specialized receptors in various tissues. While elevated cortisol levels are the defining feature of Cushing’s, there is little association between the levels of the hormone and symptom severity. This may be explained partly by the variability in the extent to which cortisol activates its receptors on different people.

“A test that measures cortisol activity at the [receptor] rather than circulating cortisol levels could yield more clinically meaningful results” the authors wrote.

The FK506-binding protein 51 (FKBP5) is a co-chaperone — a protein that assists other chaperones folding other proteins — that help regulate the activity of cortisol receptors. Previous studies also demonstrated that FKBP5 protein and RNA levels change in response to glucocorticoids, implying that FKBP5 could be a useful cortisol activity biomarker.

In the new study, a team of U.S.-based researchers examined how FKBP5 messenger RNA (mRNA) levels changed in Cushing’s patients following surgery to remove the disease-causing tumor. Of note, mRNA is the RNA molecule that cells use as a blueprint to produce a protein — in this case, FKBP5.

The study (NCT02922257) enrolled 24 patients with Cushing’s. From these, all but one had Cushing’s disease, and all but two had their cortisol and FKBP5 levels measured before and after surgery.

After surgery, 54.5% of evaluable patients had cortisol levels lower than 5 micrograms per deciliter (mcg/dL), which corresponded to a successful surgery. The remaining 45.5% had cortisol levels above this cut-off value, meaning surgery was unsuccessful.

Median cortisol levels after surgery were 1.1 mcg/dL among those in whom surgery was successful, and 12.6 mcg/dL among those in whom the procedure was unsuccessful.

Analysis revealed there was a strong positive correlation between cortisol and FKBP5 mRNA levels. In other words, individuals with high cortisol levels were statistically more likely to also have high FKBP5 mRNA levels, and vice versa.

Among individuals in whom surgery was successful, FKBP5 mRNA levels after surgery were not significantly different from those seen in healthy individuals without Cushing’s. In contrast, among patients in whom surgery was unsuccessful, FKBP5 mRNA levels remained elevated after surgery, compared with patients who had a successful surgical treatment and healthy controls.

These findings “support our hypothesis that FKBP5 can serve as a measure of cortisol biological activity and set the stage for the development of FKBP5 mRNA expression as a potential biomarker of cortisol activity in patients with [Cushing’s syndrome],” the researchers wrote.

The team noted that, if a test measuring FKBP5 mRNA levels is validated, it could “supplement or, in some cases, replace current diagnostic methods” for Cushing’s, though they emphasized the need for further testing and validation in a larger number of patients.

FKBP5 is currently being evaluated as a potential cortisol activity biomarker in the Phase 3 trials GRACE (NCT03697109) and GRADIENT (NCT04308590). Both are assessing the safety and efficacy of relacorilant, an investigational Cushing’s treatment being developed by Corcept. The studies are currently recruiting participants in North America and Europe.