Methods for diagnosing and assessing treatment for cushing's syndrome

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.

What is claimed is: 
     
         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 ceils; 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 . 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. 
     
     
         5 . The method of  claim 1 , wherein the GRA administered to the subject comprises mifepristone. 
     
     
         6 . The method of  claim 1 , wherein the GRA administered to the subject is a non-steroidal GRA. 
     
     
         7 . The method of  claim 6 , wherein the non-steroidal GRA administered to the subject is selected from the group consisting of non-steroidal GRAs having: a fused azadecalin backbone; a heteroaryl-ketone fused azadecalin backbone; an octahydro fused azadecalin backbone; and having a cyclohexyl-pyrimidine backbone. 
     
     
         8 . 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. 
     
     
         9 . The method of  claim 1 , wherein the patient is in need of administration of the glucocorticoid receptor antagonist (GRA). 
     
     
         10 . The method of  claim 9 , wherein the patient has elevated levels of cortisol. 
     
     
         11 . The method of  claim 1 , wherein the patient has cancer and the first and second samples comprise tumor cells. 
     
     
         12 . 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 in the absence of a detected reduction in the expression level of the gene encoding FKBP5 protein in the second sample. 
     
     
         13 . The method of  claim 1 , whereby said indication of a biochemical response diagnoses hypercortisolemia. 
     
     
         14 . The method of  claim 13 , further comprising administering to the patient a hypercortisolemia treatment comprising administration of a GRA to the patient. 
     
     
         15 . The method of  claim 14 , wherein said GRA administered to the patient is mifepristone. 
     
     
         16 . The method of  claim 14 , wherein said GRA administered to the patient is a non-steroidal GRA. 
     
     
         17 . The method of  claim 16 , wherein said GRA administered to the patient is a non-steroidal GRA having a fused azadecalin backbone. 
     
     
         18 . The method of  claim 16 , wherein said GRA administered to the patient is a non-steroidal GRA having a heteroaryl-ketone fused azadecalin backbone. 
     
     
         19 . The method of  claim 16 , wherein said GRA administered to the patient is a non-steroidal GRA having an octahydro fused azadecalin backbone. 
     
     
         20 . The method of  claim 16 , wherein said GRA administered to the patient is a non-steroidal GRA having a cyclohexyl-pyrimidine backbone.