Methods for diagnosing and assessing treatment for cushing's syndrome

Patent metadata

Field	Value
Publication number	US-2018291451-A1
Application number	US-201615570710-A
Country	US
Kind code	A1
Filing date	May 18, 2016
Priority date	May 18, 2015
Publication date	Oct 11, 2018
Grant date	—

Abstract

Methods are provided for assessing a clinical response to a glucocorticoid receptor antagonist (GRA) in a human subject and for diagnosing Cushing's syndrome.

First claim

1 . A method for assessing a biochemical response to a glucocorticoid receptor antagonist (GRA) in a human subject, the method comprising:
a) measuring a first amount, or activity of 51 kDa FK506 binding protein (FKBP5 protein) or a first expression level of a gene encoding FKBP5 protein in a first sample from the subject, wherein:
i) the first sample comprises primary cells; and
ii) the first sample is obtained before the GRA is administered to the subject;
b) measuring a second amount or activity of FKBP5 protein or a second expression level of a gene encoding FKBP5 protein in a second sample from the subject, wherein:
i) the second sample comprises primary cells; and
ii) the second sample is obtained after the GRA is administered to the subject; and
c) comparing the first and second amounts, activities, or expression levels, wherein a reduction in the amount or activity of FKBP5 protein or a reduction in the expression level of the gene encoding FKBP5 protein in the second sample indicates the biochemical response to the GRA.

2 . The method of claim 1 , wherein the first sample is obtained prior to administering multiple doses of GRA to the subject, and the second sample is obtained after administering the multiple doses of GRA to the subject.

3 . The method of claim 1 , wherein the measuring of a) and/or b) comprises quantitating an amount of mRNA encoding FKBP5 protein in the sample, quantitating the amount of FKBP5 protein in the sample, quantitating the amount of FKBP5 protein activity in the sample, or combinations thereof.

4 .- 5 . (canceled)

6 . The method of claim 3 , comprising quantitating the amount of FKBP5 protein activity, wherein the quantitating the amount of FKBP5 protein activity in the sample comprises measuring FKBP5 protein peptidyl-prolyl-cis-trans isomerase activity in the sample, or comprises measuring the amount of FKBP5 protein bound to glucocorticoid receptor (GR) in the sample.

7 . (canceled)

8 . The method of claim 1 , wherein the GRA administered to the subject comprises mifepristone.

9 . The method of claim 1 , wherein the GRA administered to the subject is not mifepristone.

10 . The method of claim 9 , wherein the GRA administered to the subject comprises a heteroaryl-ketone GRA.

11 . The method of claim 1 , wherein I) the first or second samples, or both, comprise whole blood, or a fraction thereof, or II) the first or second samples, or both, comprise nasal epithelial scraping samples.

12 . (canceled)

13 . The method of claim 1 , wherein the patient is in need of administration of the glucocorticoid receptor antagonist (GRA).

14 . The method of claim 13 , wherein the patient has elevated levels of cortisol.

15 . The method of claim 1 , wherein the patient has cancer and the first and second samples comprise tumor cells.

16 . (canceled)

17 . The method of claim 1 , wherein the method comprises administering an increased amount of GRA to the subject in the absence of a detected reduction in the amount or activity of FKBP5 protein or a detected reduction in the expression level of the gene encoding FKBP5 protein in the second sample.

18 . A method for diagnosing Cushing's syndrome in a human subject, the method comprising:
a) measuring an amount, or activity of 51 kDa FK506 binding protein (FKBP5 protein) or an expression level of a gene encoding FKBP5 protein in a sample obtained from the subject, wherein the sample comprises primary cells; and b) identifying the subject as likely to be suffering from Gushing's syndrome when the amount, activity or expression level is high relative to a control.

19 . The method of claim 18 , wherein the measuring comprises one or more of I) quantitating an amount of mRNA encoding FKBP5 protein in the primary cells of the sample, II) quantitating the amount of FKBP5 protein in the primary cells of the sample, and III) quantitating the FKBP5 protein activity in the primary cells of the sample.

20 . (canceled)

21 . (canceled)

22 . The method of claim 19 , comprising quantitating the FKBP5 protein activity in the primary cells of the sample, wherein the quantitating the FKBP5 protein activity in the primary cells of the sample comprises A) quantitating FKBP5 protein peptidyl-prolyl-cis-trans isomerase activity in the primary cells of the sample, or B) quantitating the FKBP5 protein activity in the primary cells of the sample comprises quantitating the amount of FKBP5 protein bound to GR in the primary cells of the sample, or both.

23 . (canceled)

24 . The method of claim 18 , wherein the sample obtained from the subject comprises whole blood, or a fraction thereof.

25 . The method of claim 18 , wherein the subject has undergone transsphenoidal surgery before the sample is obtained from the subject.

26 . The method of claim 18 , wherein the method comprises administering a treatment for Cushing's syndrome when the amount or activity of FKBP5 protein or the expression level of the gene encoding FBPS protein is high relative to a control.

27 . The method of claim 26 , wherein the administering the treatment for Cushing's syndrome comprises administering to the subject a glucocorticoid receptor antagonist (GRA).

28 . A method for assessing a biochemical response in a human subject to administering to the subject a medical or surgical therapy for treatment of hypercortisolemia, the method comprising:
a) measuring a first amount, or activity of 51 kDa FK506 binding protein (FKBP5 protein) or a first expression level of a gene encoding FKBP5 protein in a first sample from the subject, wherein:
i) the first sample comprises primary cells; and ii) the first sample is obtained before administering the medical or surgical therapy for treatment of hypercortisolemia to the subject;
b) measuring a second amount or activity of FKBP5 protein or a second expression level of a gene encoding FKBP5 protein in a second sample from the subject, wherein:
i) the second sample comprises primary cells; and
ii) the second sample is obtained after the medical or surgical therapy for treatment of hypercortisolemia is administered to the subject; and
c) comparing the first and second amounts, activities, or expression levels, wherein a reduction in the amount or activity of FKBP5 protein or a reduction in the expression level of the gene encoding FKBP5 protein in the second sample indicates the biochemical response to the medical or surgical therapy for treatment of hypercortisolemia.

29 . The method of claim 28 , wherein the medical or surgical therapy for treatment of hypercortisolemia is selected from the group consisting of: inhibition of steroidogenesis, administration of an ACTH modulator, GRA administration, transsphenoidal surgery, repeat transsphenoidal surgery, unilateral adrenalectomy, bilateral adrenalectomy, radiotherapy, resection of a non-pituitary ACTH-secreting tumor, treatment with a peptide receptor radionuclide therapy, and combinations thereof.

30 - 32 . (canceled)

33 . The method of claim 28 , wherein the method comprises administering an additional medical or surgical therapy for treatment of hypercortisolemia in an absence of a detected reduction in the amount or activity of FKBP5 protein or reduction in the expression level of the gene encoding FKBP5 protein in the second sample.

Assignees

• Corcept Therapeutics Inc

Inventors

• Belanoff Joseph K
• Hunt Hazel
• Unitt John Francis
• Moraitis Andreas G

Classifications

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C12Q1/533

  involving isomerase · CPC title

• G01N2333/99

  Isomerases (5.) · CPC title

• C12Y502/01008

  Peptidylprolyl isomerase (5.2.1.8), i.e. cyclophilin · CPC title

• A61K31/567

  substituted in position 17 alpha, e.g. mestranol, norethandrolone · CPC title