Patent Publication Number: US-2021179660-A1

Title: Glucocorticoid inhibitors for treatment of prostate cancer

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional application of U.S. patent application Ser. No. 15/103,283, filed Jun. 9, 2016, which is the national phase entry of PCT App. No. PCT/US14/69854, filed Dec. 11, 2014, which claims priority to U.S. Provisional Application No. 61/914,917, filed Dec. 11, 2013, the entirety of each of which is incorporated herein by reference. 
    
    
     GOVERNMENT SUPPORT 
     This invention was made with government support under CA155169 awarded by the National Institutes of Health and W81WH-11-1-0274 awarded by the Army Medical Research and Materiel Command. The government has certain rights in the invention. 
    
    
     SEQUENCE LISTING 
     The present application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on Apr. 21, 2015, is named 2003080_1858_Sequence_Listing.TXT and is 170 megabytes in size. 
     BACKGROUND 
     According to American Cancer Society statistics released in 2013, almost 50% of American men, and more than 30% of American women, will develop cancer in their lifetime (see Cancer Facts &amp; FIGS. 2013 from American Cancer Society Inc.,). Although remarkable progress has been made in understanding the biological basis of and in treating cancer, cancer remains second only to cardiac disease as the main cause of death in the United States. 
     Prostate cancer is the most common form of cancer in males. It typically afflicts aging males, but it can afflict males of all ages. A significant number of males die from prostate cancer every year, and it is the second leading cause of cancer deaths in men. 
     SUMMARY 
     The present invention encompasses the recognition that reproducible and detectable changes in the level and/or activity of Glucocorticoid Receptor (GR) are associated with incidence and/or risk of Castration Resistant Prostate Cancer (CRPC) and/or doubly resistant prostate cancer, particularly in individuals having prostate cancer and on antiandrogen therapy, and provides for the use of GR inhibitors to treat and/or reduce risk of CRPC and/or doubly resistant prostate cancer. In some embodiments, GR inhibitors useful in accordance with the present invention also have Androgen Receptor (AR) inhibitory activity and/or are administered in conjunction with AR inhibitors. The present invention also provides technologies for identification and/or characterization of agents to treat and/or reduce risk of CRPC and/or doubly resistant prostate cancer; in some embodiments such agents alter level and/or activity of a GR. In some embodiments, provided agents show effects on a GR&#39;s activity of regulating transcription of one or more target genes. The present invention also provides systems for using such agents, for example to treat and/or reduce risk of CRPC and/or doubly resistant prostate cancer. 
     In certain embodiments, the present disclosure provides methods for treating or reducing the risk of castration resistant prostate cancer comprising administering to a subject suffering from or susceptible to castration resistant prostate cancer a GR inhibitor. In some embodiments, the subject suffering from or susceptible to castration resistant prostate cancer is a subject who has received castration therapy. 
     In some embodiments, the present disclosure provides methods for treating or reducing the risk of doubly resistant prostate cancer comprising administering to a subject suffering from or susceptible to doubly resistant prostate cancer a GR inhibitor. In some embodiments, the subject suffering from or susceptible to doubly resistant prostate cancer is a subject who has received both castration therapy and Androgen Receptor inhibitor therapy. 
     In certain embodiments, the present disclosure provides methods for treating or reducing the risk of castration resistant prostate cancer comprising administering to a subject suffering from or susceptible to castration resistant prostate cancer a combination of a Glucocorticoid Receptor inhibitor and an Androgen Receptor inhibitor. In some embodiments, the subject suffering from or susceptible to castration resistant prostate cancer is a subject who has received castration therapy. 
     In certain embodiments, the present disclosure provides methods for treating or reducing the risk of doubly resistant prostate cancer comprising administering to a subject suffering from or susceptible to doubly resistant prostate cancer a combination of a Glucocorticoid Receptor inhibitor and an Androgen Receptor inhibitor. In some embodiments, the subject suffering from or susceptible to doubly resistant prostate cancer is a subject who has received both castration therapy and Androgen Receptor inhibitor therapy. 
     In some embodiments, according to the methods presented herein, castration therapy comprises physical castration. In some embodiments, castration therapy comprises chemical castration. In some embodiments, Androgen Receptor inhibitor therapy comprises treatment with ARN-509 and/or enzalutamide. 
     In some embodiments, according to the methods presented herein, the step of administering comprises administering to a subject whose Androgen Receptor is inhibited. In some embodiments, the Glucocorticoid Receptor inhibitor does not significantly activate Androgen Receptor levels and/or activity. In some embodiments, the Glucocorticoid Receptor inhibitor is an Androgen Receptor inhibitor. In some embodiments, the Glucocorticoid Receptor inhibitor is not an Androgen Receptor inhibitor. 
     In some embodiments, according to the methods presented herein, the Glucocorticoid Receptor inhibitor inhibits Glucocorticoid Receptor transcriptional activation activity. In some embodiments, the Glucocorticoid Receptor inhibitor is characterized in that a Glucocorticoid Receptor mRNA level is lower in a relevant Glucocorticoid Receptor expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, the Glucocorticoid Receptor inhibitor is characterized in that a Glucocorticoid Receptor protein level is lower in a relevant Glucocorticoid Receptor expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, the Glucocorticoid Receptor inhibitor is or comprises an siRNA agent that targets the Glucocorticoid Receptor. In some embodiments, the Glucocorticoid Receptor inhibitor is or comprises a short hairpin RNA (shRNA) that targets the Glucocorticoid Receptor. In some embodiments, the Glucocorticoid Receptor inhibitor is or comprises an antibody that specifically binds to the Glucocorticoid Receptor. In some embodiments, the Glucocorticoid Receptor inhibitor is or comprises a small molecule characterized in that, when the small molecule is contacted with a system expressing or capable of expressing Glucocorticoid Receptor, level and/or activity of Glucocorticoid Receptor in the system is reduced when the small molecule is present as compared with a reference level or activity observed under otherwise comparable conditions when it is absent. In some embodiments, the Glucocorticoid Receptor inhibitor is selected from the group consisting of RU-486 and ORG 34517. In some embodiments, the Glucocorticoid Receptor inhibitor is selected from the group consisting of analogs of RU-486. In some embodiments, the Glucocorticoid Receptor inhibitor is selected from the group consisting of analogs of ORG 34517. In some embodiments, the Glucocorticoid Receptor inhibitor 
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
     In some embodiments, according to the methods presented herein, the Androgen Receptor inhibitor inhibits Androgen Receptor transcriptional activation activity. In some embodiments, the Androgen Receptor inhibitor is characterized in that an Androgen Receptor mRNA level is lower in a relevant Androgen Receptor expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, the Androgen Receptor inhibitor is characterized in that an Androgen Receptor protein level is lower in a relevant Androgen Receptor expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, the Androgen Receptor inhibitor is or comprises an siRNA agent that targets the Androgen Receptor. In some embodiments, the Androgen Receptor inhibitor is or comprises a short hairpin RNA (shRNA) that targets the Androgen Receptor. In some embodiments, the Androgen Receptor inhibitor is or comprises an antibody that specifically binds to the Androgen Receptor. In some embodiments, the Androgen Receptor inhibitor is or comprises a small molecule characterized in that, when the small molecule is contacted with a system expressing or capable of expressing Androgen Receptor, level and/or activity of Androgen Receptor in the system is reduced when the small molecule is present as compared with a reference level or activity observed under otherwise comparable conditions when it is absent. In some embodiments, the Androgen Receptor inhibitor is selected from the group consisting of 3,3′-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, and/or turosteride. 
     In some embodiments, the present disclosure provides methods for identifying or characterizing agents for the treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer comprising contacting a system in which Glucocorticoid Receptor and Androgen Receptor are present and active with at least one test agent, determining a level or activity of Glucocorticoid Receptor in the system when the agent is present as compared with a Glucocorticoid Receptor reference level or activity observed under otherwise comparable conditions when it is absent, determining a level or activity of Androgen Receptor in the system when the agent is present as compared with an Androgen Receptor reference level or activity observed under otherwise comparable conditions when it is absent, and classifying the at least one test agent as a treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer if the level or activity of Glucocorticoid Receptor is significantly reduced when the test agent is present as compared with the Glucocorticoid Receptor reference level or activity and the Androgen Receptor is not significantly increased when the test agent is present as compared with the Androgen Receptor reference level or activity. In some embodiments, the test agent is classified as a treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer if the level or activity of Androgen Receptor is significantly reduced when the test agent is present as compared with the Androgen Receptor reference level or activity. In some embodiments, the level or activity of Glucocorticoid Receptor comprises a Glucocorticoid Receptor mRNA level. In some embodiments, the level or activity of Androgen Receptor comprises a Androgen Receptor mRNA level. In some embodiments, the level or activity of Glucocorticoid Receptor comprises a Glucocorticoid Receptor protein level. In some embodiments, the level or activity of Androgen Receptor comprises a Androgen Receptor protein level. In some embodiments, a significant reduction in the level or activity of Glucocorticoid Receptor comprises a greater than 50% reduction of Glucocorticoid Receptor activity. In some embodiments, a significant reduction in the level or activity of Glucocorticoid Receptor comprises a greater than 50% reduction of Glucocorticoid Receptor levels. In some embodiments, a significant reduction in the level or activity of Androgen Receptor comprises a greater than 50% reduction of Androgen Receptor activity. In some embodiments, a significant reduction in the level or activity of Androgen Receptor comprises a greater than 50% reduction of Androgen Receptor levels. In some embodiments, the test agent is or comprises an siRNA. In some embodiments, the test agent is or comprises a short hairpin RNA (shRNA). In some embodiments, the test agent is or comprises a polypeptide. In some embodiments, the test agent is or comprises an antibody. In some embodiments, the test agent is or comprises a small molecule. In some embodiments, the at least one test agent is or comprises a set of test agents that show significant structural similarity and discrete structural differences such that the step of determining, when performed for the set of test agents, establishes a structure-function relationship between one or more structural elements present within the set of test agents and Glucocorticoid Receptor inhibitory activity. 
     In some embodiments, the present disclosure provides compounds of formula I′: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein each R 1  is independently selected from halogen, optionally substituted C 1-6 aliphatic, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(R) 3 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , SO 2 N(R) 2 , OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, and OC(O)N(R) 2 ; or two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 5- to 7-membered ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; and R 2  is optionally substituted unsaturated C 2-6 aliphatic; and each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl; and n is from 0-4. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
         FIGS. 1A-1E  demonstrate that GR mRNA and protein is expressed in resistant tissues. A. Most differentially expressed genes in a pilot cohort of LnCaP/AR xenograft tumors with acquired resistance to ARN-509 (n=6) or RD162 (n=9) compared to control (n=3) determined by microarray (Affymetrix Ex1.0). Mice with resistant tissues were continued on drug treatment through time of harvest. In vitro androgen-induced or -repressed genes are annotated. B. Mean tumor volumes+/−s.e.m of LnCaP/AR xenografts in validation cohort. Days tumors were harvested are annotated on x-axis (long hash mark). C. RT-qPCR analysis of GR and AR mRNA expression in a validation cohort of LnCaP/AR xenograft tumors from mice treated with vehicle (control, n=10), 4 days of anti-androgen (n=8), or with acquired resistance to 10 mg/kg enzalutamide (n=8) or 10 mg/kg ARN-509 (n=8). D. Western blot analysis of GR and AR protein expression in a subset of tissues also analyzed in B. Control (n=6), 4 day (n=5), Resistant (n=13). Resistant samples were loaded for protein analysis from highest to lowest GR levels based on corresponding mRNA analysis. E. Intracellular GR flow cytometric analysis of LnCaP/AR, CS1, and LREX′, cells passaged in vitro, under standard passage conditions (see methods). 
         FIGS. 2A-2B  show AR Expression in LREX′ cells. A. Indicated cells were cultured in vitro, in charcoal stripped media without enzalutamide for 3 days and then analyzed for AR expression by intracellular AR flow cytometric analysis. B. LnCaP/AR control xenografts (n=6, same samples as in  FIG. 1D ) or enzalutamide (10 mg/kg) treated LREX′ xenografts (n=8) were analyzed by GR and AR western blot. AR western blot signals were quantified using Image J software. 
         FIGS. 3A-3F  show GR is necessary for resistance in the LREX′ xenograft model. A. Mean tumor volume+/−s.e.m. of LREX′ (n=20) or LnCaP/AR (n=14) cells in castrate mice treated with 10 mg/kg enzalutamide B. Mean tumor volumes+/−s.e.m. of CS1 in castrate mice treated with vehicle (n=10) or 10 mg/kg ARN-509 (n=10). C. GR immunohistochemisty (IHC) of enzalutamide (10 mg/kg)-treated LREX′ tumors and vehicle-treated LnCaP/AR xenograft tissues. Blue arrow=endothelial/stromal cells, Black arrow=epithelial cell. D. Mean tumor volumes+/−s.e.m of LREX′ xenografts in 10 mg/kg enzalutamide-treated castrated mice after infection with a non-targeting (n=14) or GR-targeting (n=12) hairpin. Comparison is by Mann-Whitney test. E. Tumor growth curve of CS1 in castrate mice after infection with the non-targeting (n=20) or GR-targeting (n=20) hairpin. F. Western blot analysis of GR expression in LREX′ cells prior to implantation and of available tissues from D at day 49. 
         FIG. 4  shows GR induction dichotomized based on PSA response. GR IHC scores in matched baseline and 8 week samples dichotomized based on maximal PSA response +/−s.e.m. Comparisons are by Mann-Whitney test. 
         FIGS. 5A-5E  demonstrate GR induction in disseminated tumor cells is associated with poor clinical response to enzalutamide and persistence of PSA. A. Schematic of sample acquisition timeline and response groups. B. Number of good or poor responders who achieved PSA decline greater than 50%. C. Examples of GR IHC images from matched samples at baseline and 8 weeks. D. Percent GR positive epithelial cells in all tissue available at 0 and 8 weeks or E. matched samples obtained from the same patient at 0 and 8 weeks+/−s.e.m. Comparisons are by Mann-Whitney test. 
         FIG. 6  presents expression of AR target genes in resistant tumors from validation cohort. Normalized expression array signal (Illumina HT-12) of a suite of 74 AR target genes in control (n=10), 4 day (n=8), and resistant tissues from the validation cohort described in  FIG. 1  (n=12 of 16). The bottom quartile of GR expressing tissues were excluded from the analysis of the validation cohort tissues to minimize contamination from other resistance drivers. Genes are ranked by degree of restoration of expression in resistant tissue (Res-4 day)/(Control-4 day). All resistant tissues were continued on anti-androgen treatment through time of harvest. 
         FIGS. 7A-7D  demonstrates variable expression of AR target genes in LREX′, in vivo, and after glucocorticoid treatment, in vitro. A. Normalized expression array signal (Illumina HT-12) of a suite of 74 AR target genes in control (n=10), 4 day (n=8), and LREX′ (n=8, right) xenograft tumors. Genes are ranked by degree of restoration of expression in resistant tissue ((Res-4 day)/(Control-4 day)). All resistant tissues were continued on anti-androgen treatment through time of harvest. B. Fractional restoration values of each of the 74 AR targets in LREX′ xenografts (n=8) or resistant tissues from the validation cohort (n=12). C. GR mRNA in resistant tissues used in B. D. Expression of AR target genes in the LREX′ cell line in steroid depleted media after 8 hours of treatment with the indicated agonists, in vitro. Enzalutamide=10 micromolar, V=Vehicle. +/−s.e.m. 
         FIGS. 8A-8D  show that dexamethasone activity is GR, and not AR, dependent. A. LnCaP/AR cells engineered to express GFP or GR were treated with indicated drugs. B. Western blot confirmation of GR expression in cells used in A. C. Co-treatment of LREX′ cells with Dex and compound 15 and assessment of target gene expression. D. Control or AR siRNA knock-down in LREX′ followed by treatment with indicated drugs. For S4A-S4D: V=Vehicle, DHT=1 nM, Dex=100 nM (unless otherwise indicated), CMP 15=1 micromolar, Enz=10 micromolar. Cells were treated in charcoal stripped media. Expression determined by RT-qPCR +/−s.e.m. 
         FIGS. 9A-9F  show comparative AR and GR transcriptome and cistrome analysis in LREX′. A. Venn diagram of AR and GR signature gene lists. AR or GR signatures were defined as all genes showing &gt;1.6 (or &lt;−1.6) fold change (FDR&lt;0.05) after 8 hours of addition of DHT (1 nM) or Dex (100 nM) to charcoal stripped media, respectively. B. Heat map depiction of expression changes of AR signature genes (left) or GR signature genes (right) associated with the indicated treatment. Enzalutamide=10 micromolar. C. Expression of AR- or GR-induced signature genes (as defined in A.) were compared in DHT (1 nM) or Dex (100 nM) treated samples. GR signature genes that also had higher expression in Dex samples (&gt;1.1 fold, FDR&lt;0.05) were designated as GR-selective (n=67) and AR signature genes that showed higher expression in DHT samples (&gt;1.1 fold, FDR&lt;0.05) were designated as AR-selective (n=39). D. Expression of AR- and GR-selective genes in LREX′ and control tumors in vivo compared by Gene Set Enrichment Analysis (GSEA). E. AR cistrome defined by AR ChIP-seq after DHT (1 nM) treatment of LREX′ in vitro in charcoal stripped media. Percent of AR defined peaks that overlap with GR peaks found by GR ChIP-seq after Dex (100 nm) treatment of LREX′ in vitro are shown in pie graph. Top binding motifs in AR-unique and AR/GR overlap peaks are indicated below. F. GR cistrome defined by GR ChIP-seq after Dex treatment of LREX′ in vitro in charcoal stripped media. Percent of GR peaks that overlap with AR peaks found by AR ChIP-seq after DHT (1 nM) treatment of LREX′ in vitro are shown in pie graph. Top binding motifs in GR-unique and AR/GR overlap peaks are indicated below. 
         FIGS. 10A-10D  show comparative AR and GR cistrome analysis. A. ChIP-seq signal strength for AR or GR at unique and overlap peaks in the AR or GR defined cistromes. B. AR and GR ChIP-qPCR at indicated AR target genes after treatment of LREX′ in steroid depleted media with DHT (1 nm), Dex (100 nM), and/or enzalutamide (10 micromolar) for 1 hour as indicated+/−s.d. C. Integration of transcriptome and cistrome analysis. 56 AR signature genes transcriptionally regulated by DHT in LREX′ were also found to have AR binding peak. Of those, 49 also showed at least modest regulation by Dex (1.2 fold, p&lt;0.05). The percent of the 49 genes showing Dex regulation (yes) or the 7 showing no Dex regulation (no) that have an AR/GR overlap peak is shown. 
         FIGS. 11A-1111  demonstrate that GR activity is sufficient to confer enzalutamide resistance in VCaP. FOR ALL PANELS: VCaP cells do not tolerate charcoal stripped media and were cultured in standard culture conditions (fetal bovine serum with endogenous hormones). Enz=10 micromolar, Dex=100 nM, CMP 15=1 micromolar. A. Western blot analysis of prostate cancer cell lines. B, C and D. Cell viability assessed by CellTiter-Glo (Promega) assay and normalized to day 1 value after indicated treatments+/−s.e.m. E. Confirmation of GR knock-down by western blot after infection with GR targeting shRNA. F. Apoptosis as assessed by cPARP western blot after 3 days of indicated treatment. G. A suite of AR targets relevant to VCaP was defined (see methods) and normalized expression of each gene after 24 hours of indicated drug treatments is depicted by heat map and ranked by degree of induction with Dex. H. Expression of the top two genes from B. (KLK2 and FKBP5) after 24 hours of indicated treatments+/−s.e.m. 
         FIGS. 12A-12C  show GR expression and activity in VCaP. A. GR IHC of VCAP of cells in standard media treated with vehicle or Dex 100 nM+Enz 10 micromolar for 30 minutes prior to fixation. B. KLK3(PSA) western blots of VCaP lysates generated from cells in standard media treated with indicated drugs for 3 days. DHT=0.1 nM, Dex concentrations are indicated (nM), Enz=10 micromolar. C. Expression analysis using RT-qPCR of VCaP infected with a non-targeting or GR-targeting hairpin. Cells were treated in standard media as indicated for 24 hours prior to harvest. Dex=100 nM, Enz=10 micro-molar. +/−s.e.m. 
         FIGS. 13A-13G  show resistant cells are primed for GR induction upon AR inhibition. A. GR mRNA in LREX′ xenografts. Tumors were injected into castrated mice and immediately treated with 10 mg/kg enzalutamide (n=20) for 7 weeks. Half of the mice were then continued on 10 mg/kg enzalutamide (n=10) or discontinued for 8 days (n=10). B. LREX′ are maintained in vitro in the presence of enzalutamide 1 micromolar. GR mRNA was assessed in LREX′ cell line after passage for indicate number of days in standard fetal bovine serum containing media without enzalutamide. C. GR mRNA in LREX′ cultured in charcoal stripped media for 48 hours and then treated for 8 hours with vehicle or DHT with or without 10 micromolar enzalutamide. D. AR ChIP-qPCR with LREX′ cultured in charcoal stripped media and then treated for 1 hour with DHT (1 nM) or Dex (100 nM) at an intronic enhancer site+/−s.d. E. Intracellular GR flow cytometric analysis of indicated cells at indicated times points. AUC=area under curve. Enzalutamide=1 micromolar F. Plotted median fluorescence (minus background) values from E and  FIG. 14C . For both LREX plots, R 2  values for non-linear regression analysis is &gt;0.98. G. Model of GR induction in resistant tissues. 
         FIGS. 14A-14C  shows GR expression in resistant and sensitive cells A. GR intracellular staining and flow cytometric analysis of LREX′ or LREX′ off  cells after either vehicle (left) or 1 micromolar enzalutamide (right) treatment for indicated time. B. Relative cell numbers determined by cell counting (Vi-cell) of indicated cells with vehicle or 1 micro-molar enzalutamide treatment. C. Intracellular GR flow cytometric analysis of indicated cells at indicated times points. AUC=area under curve. Enzalutamide=1 micromolar. 
         FIG. 15  shows assays measuring AB173, ABR167, and ORG34517 with different concentrations of dexamethasone (Dex). 
         FIG. 16  shows effect of ABR167 and ABR173 at reversing the effect of Dex. 
         FIG. 17  shows agonist ability of ABR173 and ABR167. 
         FIG. 18  shows effectiveness of ABR173 and ABR167 as compared to Enz/ARN-509. 
         FIG. 19  shows that ABR173 and ABR167 were not as effectively antagonistic as Enz/ARN-509 in cells engineered to overexpress AR. 
         FIG. 20  shows that in LNCAP cells that overexpress the AR mutant AR F876L, the novel compounds ABR173 and ABR167 were more effective antagonists than Enz/ARN-509. 
         FIG. 21  shows that all 3 genes examined were induced by Dex and both ABRl 73 and ABR167 demonstrated mild agonist activity. 
         FIG. 22  shows that both ABR173 and ABR167 blocked the Dex induced resistance to Enz without compromising Enz function. 
         FIG. 23  shows that higher doses of ABR173 appear to slightly impair Enz efficacy. 
         FIG. 24  shows that both ABR173 and ABRl 67 appeared to cause some GR protein degradation. 
         FIG. 25  shows certain compounds. 
         FIG. 26  shows designed and modeled derivatives. 
         FIG. 27  shows a summary of 10-ns MD simulations. 
     
    
    
     DEFINITIONS 
     Agent: The term “agent” as used herein may refer to a compound or entity of any chemical class including, for example, polypeptides, nucleic acids, saccharides, lipids, small molecules, metals, or combinations thereof. As will be clear from context, in some embodiments, an agent can be or comprise a cell or organism, or a fraction, extract, or component thereof. In some embodiments, an agent is agent is or comprises a natural product in that it is found in and/or is obtained from nature. In some embodiments, an agent is or comprises one or more entities that is man-made in that it is designed, engineered, and/or produced through action of the hand of man and/or is not found in nature. In some embodiments, an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form. In some embodiments, potential agents are provided as collections or libraries, for example that may be screened to identify or characterize active agents within them. Some particular embodiments of agents that may be utilized in accordance with the present invention include small molecules, antibodies, antibody fragments, aptamers, siRNAs, shRNAs, DNA/RNA hybrids, antisense oligonucleotides, ribozymes, peptides, peptide mimetics, small molecules, etc. In some embodiments, an agent is or comprises a polymer. In some embodiments, an agent is not a polymer and/or is substantially free of any polymer. In some embodiments, an agent contains at least one polymeric moiety. In some embodiments, an agent lacks or is substantially free of any polymeric moiety. 
     Analog: As used herein, the term “analog” refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, an analog is a substance that can be generated from the reference substance by chemical manipulation of the reference substance. In some embodiments, an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference substance. In some embodiments, an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance. 
     Androgen: The term “androgen” is used herein to refer to an agent that has androgenic activity. Androgenic activity may be determined or characterized in any of a variety of ways, including in any of a variety of biological activity assays (e.g., in vitro or in vivo assays, for example utilizing animals and/or animal tissues) in which the agent is observed to have one or more activities similar or comparable to that of a known (i.e., reference) androgen assessed under comparable conditions (whether simultaneously or otherwise). In some embodiments, androgenic activity is or comprises transcriptional regulation (e.g., activation) of an androgen-responsive target gene. In some embodiments, androgenic activity is or comprises binding to an androgen receptor. In some embodiments, androgenic activity is or comprises stimulation of prostate growth in rodents. Exemplary known androgens include, for example, androstanedione, androstenediol, androstenedione, androsterone, dehydroepiandrosterone, dihydrotestosterone (DHT), and testosterone. 
     Antiandrogen: As used herein, the term “antiandrogen” is used herein to refer to an agent that inhibits. androgenic activity In some embodiments, inhibiting androgenic activity is or comprises inhibiting biological activity of an AR. In some embodiments, inhibiting androgenic activity is or comprises competing with one or more androgens for binding to an AR. Exemplary known antiandrogens include, for example, 3,3′-diindolylmethane (DIM), bexlosteride, bicalutamide, dutasteride, epristeride, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, and/or turosteride. In some embodiments, antiandrogens comprise second generation antiandrogens. Exemplary second generation antiandrogens include but are not limited to ARN-509 and enzalutamide. 
     Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone. 
     Antibody: As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As is known in the art, intact antibodies as produced in nature are approximately 150 kD tetrameric agents comprised of two identical heavy chain polypeptides (about 50 kD each) and two identical light chain polypeptides (about 25 kD each) that associate with each other into what is commonly referred to as a “Y-shaped” structure. Each heavy chain is comprised of at least four domains (each about 110 amino acids long) an amino-terminal variable (VH) domain (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y&#39;s stem). A short region, known as the “switch”, connects the heavy chain variable and constant regions. The “hinge” connects CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy chain polypeptides to one another in an intact antibody. Each light chain is comprised of two domains an amino-terminal variable (VL) domain, followed by a carboxy-terminal constant (CL) domain, separated from one another by another “switch”. Intact antibody tetramers are comprised of two heavy chain-light chain dimers in which the heavy and light chains are linked to one another by a single disulfide bond; two other disulfide bonds connect the heavy chain hinge regions to one another, so that the dimers are connected to one another and the tetramer is formed. Naturally-produced antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an “immunoglobulin fold” formed from two beta sheets (e.g., 3-, 4-, or 5-stranded sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as “complement determining regions” (CDR1, CDR2, and CDR3) and four somewhat invariant “framework” regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions from both the heavy and light chains are brought together in three-dimensional space so that they create a single hypervariable antigen binding site located at the tip of the Y structure. Amino acid sequence comparisons among antibody polypeptide chains have defined two light chain (κ and λ) classes, several heavy chain (e.g., μ, γ, α, ε, δ) classes, and certain heavy chain subclasses (α1, α2, γ1, γ2, γ3, and γ4). Antibody classes (IgA [including IgA1, IgA2], IgD, IgE, IgG [including IgG1, IgG2, IgG3, IgG4], IgM) are defined based on the class of the utilized heavy chain sequences. For purposes of the present invention, in certain embodiments, any polypeptide or complex of polypeptides that includes sufficient immunoglobulin domain sequences as found in natural antibodies can be referred to and/or used as an “antibody”, whether such polypeptide is naturally produced (e.g., generated by an organism reacting to an antigen), or produced by recombinant engineering, chemical synthesis, or other artificial system or methodology. In some embodiments, an antibody is monoclonal; in some embodiments, an antibody is polyclonal. In some embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, an antibody sequence elements are humanized, primatized, chimeric, etc., as is known in the art. Moreover, the term “antibody” as used herein, (unless otherwise stated or clear from context) can refer in appropriate embodiments to any of the art-known or developed constructs or formats for capturing antibody structural and functional features in alternative presentation. For example, in some embodiments, the term can refer to bi- or other multi-specific (e.g., zybodies, etc) antibodies, Small Modular ImmunoPharmaceuticals (“SMIPs™”), single chain antibodies, cameloid antibodies, and/or antibody fragments. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload [e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc], or other pendant group [e.g., poly-ethylene glycol, etc]. 
     Antibody fragment: As used herein, an “antibody fragment” includes a portion of an intact antibody, such as, for example, the antigen-binding or variable region of an antibody. Examples of antibody fragments include Fab, Fab′, F(ab′)2, and Fv fragments; triabodies; tetrabodies; linear antibodies; single-chain antibody molecules; and CDR-containing moieties included in multi-specific antibodies formed from antibody fragments. Those skilled in the art will appreciate that the term “antibody fragment” does not imply and is not restricted to any particular mode of generation. An antibody fragment may be produced through use of any appropriate methodology, including but not limited to cleavage of an intact antibody, chemical synthesis, recombinant production, etc. 
     Approximately: As used herein, the term “approximately” and “about” is intended to encompass normal statistical variation as would be understood by those of ordinary skill in the art as appropriate to the relevant context. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). 
     Associated with: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and/or form correlates with incidence of and/or susceptibility of the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof. 
     Carrier: As used herein, the term “carrier” refers to a pharmaceutically acceptable (e.g., safe and non-toxic for administration to a human) carrier substance useful for preparation of a pharmaceutical formulation. In many embodiments, a carrier is biologically substantially inert, e.g., so that activity of a biologically active substance is not materially altered in its presence as compared with in its absence. In some embodiments, a carrier is a diluent. 
     Comparable: The term “comparable” as used herein refers to a system, set of conditions, effects, or results that is/are sufficiently similar to a test system, set of conditions, effects, or results, to permit scientifically legitimate comparison. Those of ordinary skill in the art will appreciate and understand which systems, sets of conditions, effect, or results are sufficiently similar to be “comparable” to any particular test system, set of conditions, effects, or results as described herein. 
     Derivative: As used herein, the term “derivative” refers to a structural analogue of a reference substance. That is, a “derivative” is a substance that shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways. In some embodiments, a derivative is a substance that can be generated from the reference substance by chemical manipulation. In some embodiments, a derivative is a substance that can be generated through performance of a synthetic process substantially similar to (e.g., sharing a plurality of steps with) one that generates the reference sub stance. 
     Designed: As used herein, the term “designed” refers to an agent (i) whose structure is or was selected by the hand of man; (ii) that is produced by a process requiring the hand of man; and/or (iii) that is distinct from natural substances and other known agents. 
     Docking: As used herein, the term “docking” refers to orienting, rotating, translating a chemical entity in the binding pocket, domain, molecule or molecular complex or portion thereof based on distance geometry or energy. Docking may be performed by distance geometry methods that find sets of atoms of a chemical entity that match sets of sphere centers of the binding pocket, domain, molecule or molecular complex or portion thereof. See Meng et al. J. Comp. Chem. 4: 505-524 (1992). Sphere centers are generated by providing an extra radius of given length from the atoms (excluding hydrogen atoms) in the binding pocket, domain, molecule or molecular complex or portion thereof. Real-time interaction energy calculations, energy minimizations or rigid-body minimizations (Gschwend et al., J. Mol. Recognition 9:175-186 (1996)) can be performed while orienting the chemical entity to facilitate docking. For example, interactive docking experiments can be designed to follow the path of least resistance. If the user in an interactive docking experiment makes a move to increase the energy, the system will resist that move. However, if that user makes a move to decrease energy, the system will favor that move by increased responsiveness. (Cohen et al., J. Med. Chem. 33:889-894 (1990)). Docking can also be performed by combining a Monte Carlo search technique with rapid energy evaluation using molecular affinity potentials. See Goodsell and Olson, Proteins: Structure, Function and Genetics 8:195-202 (1990). Software programs that carry out docking functions include but are not limited to MATCHMOL (Cory et al., J. Mol. Graphics 2: 39 (1984); MOLFIT (Redington, Comput. Chem. 16: 217 (1992)) and DOCK (Meng et al., supra). 
     Dosage form: As used herein, the terms “dosage form” and “unit dosage form” refer to a physically discrete unit of a therapeutic composition for administration to a subject to be treated. Each unit dosage form contains a predetermined quantity of active agent calculated to produce a desired therapeutic effect when administered in accordance with a dosing regimen. It will be understood, however, that a total dosage of the active agent may be decided by an attending physician within the scope of sound medical judgment. 
     Dosing regimen: A “dosing regimen” (or “therapeutic regimen”), as that term is used herein, is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, the therapeutic agent is administered continuously over a predetermined period. In some embodiments, the therapeutic agent is administered once a day (QD) or twice a day (BID). 
     Fragment: A “fragment” of a material or entity as described herein has a structure that includes a discrete portion of the whole, but lacks one or more moieties found in the whole. In some embodiments, a fragment consists of such a discrete portion. In some embodiments, a fragment consists of or comprises a characteristic structural element or moiety found in the whole. In some embodiments, a polymer fragment comprises or consists of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., residues) as found in the whole polymer. In some embodiments, a polymer fragment comprises or consists of at least about 5%, 10%, 15%, 20%, 25%, 30%, 3535%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the whole polymer. The whole material or entity may in some embodiments be referred to as the “parent” of the whole. 
     Improve, increase, or reduce: As used herein, the terms “improve,” “increase” or “reduce,” or grammatical equivalents, indicate a change in a value relative to a comparable baseline or reference measurement. In some embodiments, a comparable baseline or reference measurement is a measurement taken in the same system (e.g., of the same individual) prior to initiation of an event of interest (e.g., of therapy). In some embodiments, a comparable baseline or reference measurement is one taken in a different system (e.g., a different individual or cell) under otherwise identical conditions (e.g., in a normal cell or individual as compared with one suffering from or susceptible to a particular disease, disorder or condition, for example due to presence of a particular genetic mutation). 
     In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism. 
     In vivo: As used herein, the term “in vivo” refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems). 
     Inhibitor: The term “inhibitor” is used to refer to an entity whose presence in a system in which an activity of interest is observed correlates with a decrease in level and/or nature of that activity as compared with that observed under otherwise comparable conditions when the inhibitor is absent. In some embodiments, an inhibitor interacts directly with a target entity whose activity is of interest. In some embodiments, an inhibitor interacts indirectly (i.e., directly with an intermediate agent that interacts with the target entity) with a target entity whose activity is of interest. In some embodiments, an inhibitor affects level of a target entity of interest; alternatively or additionally, in some embodiments, an inhibitor affects activity of a target entity of interest without affecting level of the target entity. In some embodiments, an inhibitor affects both level and activity of a target entity of interest, so that an observed difference in activity is not entirely explained by or commensurate with an observed difference in level. 
     Isolated: As used herein, the term “isolated” is used to refer to a substance and/or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature and/or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, substantially 100%, or 100% of the other components with which they were initially associated. In some embodiments, isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, substantially 100%, or 100% pure. As used herein, a substance is “pure” if it is substantially free of other components. As used herein, the term “isolated cell” refers to a cell not contained in a multi-cellular organism. 
     Nucleic Acid: As used herein, the term “nucleic acid,” in its broadest sense, refers to any compound and/or substance that is or can be incorporated into an oligonucleotide chain. In some embodiments, a nucleic acid is a compound and/or substance that is or can be incorporated into an oligonucleotide chain via a phosphodiester linkage. As will be clear from context, in some embodiments, “nucleic acid” refers to individual nucleic acid residues (e.g., nucleotides and/or nucleosides); in some embodiments, “nucleic acid” refers to an oligonucleotide chain comprising individual nucleic acid residues. In some embodiments, a “nucleic acid” is or comprises RNA; in some embodiments, a “nucleic acid” is or comprises DNA. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleic acid residues. In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleic acid analogs. In some embodiments, a nucleic acid analog differs from a nucleic acid in that it does not utilize a phosphodiester backbone. For example, in some embodiments, a nucleic acid is, comprises, or consists of one or more “peptide nucleic acids”, which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone, are considered within the scope of the present invention. Alternatively or additionally, in some embodiments, a nucleic acid has one or more phosphorothioate and/or 5′-N-phosphoramidite linkages rather than phosphodiester bonds. In some embodiments, a nucleic acid is, comprises, or consists of one or more natural nucleosides (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine). In some embodiments, a nucleic acid is, comprises, or consists of one or more nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a nucleic acid comprises one or more modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or protein. In some embodiments, a nucleic acid includes one or more introns. In some embodiments, nucleic acids are prepared by one or more of isolation from a natural source, enzymatic synthesis by polymerization based on a complementary template (in vivo or in vitro), reproduction in a recombinant cell or system, and chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues long. 
     Polypeptide: The term “polypeptide”, as used herein, generally has its art-recognized meaning of a polymer of at least three amino acids. Those of ordinary skill in the art will appreciate that the term “polypeptide” is intended to be sufficiently general as to encompass not only polypeptides having a complete sequence recited herein, but also to encompass polypeptides that represent functional fragments (i.e., fragments retaining at least one activity) of such complete polypeptides. Moreover, those of ordinary skill in the art understand that protein sequences generally tolerate some substitution without destroying activity. Thus, any polypeptide that retains activity and shares at least about 30-40% overall sequence identity, often greater than about 50%, 60%, 70%, or 80%, and further usually including at least one region of much higher identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99% in one or more highly conserved regions, usually encompassing at least 3-4 and often up to 20 or more amino acids, with another polypeptide of the same class, is encompassed within the relevant term “polypeptide” as used herein. Polypeptides may contain L-amino acids, D-amino acids, or both and may contain any of a variety of amino acid modifications or analogs known in the art. Useful modifications include, e.g., terminal acetylation, amidation, methylation, etc. In some embodiments, proteins may comprise natural amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. The term “peptide” is generally used to refer to a polypeptide having a length of less than about 100 amino acids, less than about 50 amino acids, less than 20 amino acids, or less than 10 amino acids. In some embodiments, proteins are antibodies, antibody fragments, biologically active portions thereof, and/or characteristic portions thereof. 
     Protein: The term “protein” as used herein refers to one or more polypeptides that function as a discrete unit. If a single polypeptide is the discrete functioning unit and does not require permanent or temporary physical association with other polypeptides in order to form the discrete functioning unit, the terms “polypeptide” and “protein” may be used interchangeably. If the discrete functional unit is comprised of more than one polypeptide that physically associate with one another, the term “protein” may be used to refer to the multiple polypeptides that are physically associated and function together as the discrete unit. In some embodiments, proteins may include moieties other than amino acids (e.g., may be glycoproteins, proteoglycans, etc.) and/or may be otherwise processed or modified. Those of ordinary skill in the art will appreciate that in some embodiments the term “protein” may refer to a complete polypeptide chain as produced by a cell (e.g., with or without a signal sequence), and/or to a form that is active within a cell (e.g., a truncated or complexed form). In some embodiments where a protein is comprised of multiple polypeptide chains, such chains may be covalently associated with one another, for example by one or more disulfide bonds, or may be associated by other means. 
     Reference: The term “reference” is often used herein to describe a standard or control agent, individual, population, sample, sequence or value against which an agent, individual, population, sample, sequence or value of interest is compared. In some embodiments, a reference agent, individual, population, sample, sequence or value is tested and/or determined substantially simultaneously with the testing or determination of the agent, individual, population, sample, sequence or value of interest. In some embodiments, a reference agent, individual, population, sample, sequence or value is a historical reference, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference agent, individual, population, sample, sequence or value is determined or characterized under conditions comparable to those utilized to determine or characterize the agent, individual, population, sample, sequence or value of interest. 
     Risk: As will be understood from context, a “risk” of a disease, disorder or condition is a degree of likelihood that a particular individual will develop the disease, disorder, or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 100%. In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some embodiments, a reference sample or group of reference samples have a known risk of a disease, disorder, or condition. In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual. In some embodiments, relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. 
     Sample: As used herein, the term “sample” typically refers to a biological sample obtained or derived from a source of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and/or excretions; and/or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc. 
     Small molecule: As used herein, the term “small molecule” means a low molecular weight organic compound that may serve as an enzyme substrate or regulator of biological processes. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, provided nanoparticles further include one or more small molecules. In some embodiments, the small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, one or more small molecules are encapsulated within the nanoparticle. In some embodiments, small molecules are non-polymeric. In some embodiments, in accordance with the present invention, small molecules are not proteins, polypeptides, oligopeptides, peptides, polynucleotides, oligonucleotides, polysaccharides, glycoproteins, proteoglycans, etc. In some embodiments, a small molecule is a therapeutic. In some embodiments, a small molecule is an adjuvant. In some embodiments, a small molecule is a drug. 
     Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. 
     Suffering from: An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with and/or displays one or more symptoms of the disease, disorder, and/or condition. 
     Therapeutic agent: As used herein, the phrase “therapeutic agent” refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if its administration to a relevant population is statistically correlated with a desired or beneficial therapeutic outcome in the population, whether or not a particular subject to whom the agent is administered experiences the desired or beneficial therapeutic outcome. 
     Therapeutically effective amount: As used herein, the term “therapeutically effective amount” refers to an amount of an agent which confers a therapeutic effect on a treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. A therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). In particular, a “therapeutically effective amount” refers to an amount of a therapeutic agent effective to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect, such as by ameliorating symptoms associated with a disease, preventing or delaying onset of a disease, and/or also lessening severity or frequency of symptoms of a disease. A therapeutically effective amount is commonly administered in a dosing regimen that may comprise multiple unit doses. For any particular therapeutic agent, a therapeutically effective amount (and/or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, on combination with other agents. Also, a specific therapeutically effective amount (and/or unit dose) for any particular patient may depend upon a variety of factors including what disorder is being treated; disorder severity; activity of specific agents employed; specific composition employed; age, body weight, general health, and diet of a patient; time of administration, route of administration; treatment duration; and like factors as is well known in the medical arts. 
     Therapeutic regimen: A “therapeutic regimen”, as that term is used herein, refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome. 
     Treatment: As used herein, the term “treatment” (also “treat” or “treating”) refers to any administration of a substance that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces frequency, incidence or severity of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition. 
     Vector: As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors include, e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses. 
     Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th  Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March&#39;s Advanced Organic Chemistry”, 5 th  Ed., Ed.: Smith, M. B. and March, J., John Wiley &amp; Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. 
     The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. 
     The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C 3 -C 7  hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. 
     The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +  (as in N-substituted pyrrolidinyl)). 
     The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. 
     The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH 2 ) n —, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. 
     The term “halogen” means F, Cl, Br, or I. 
     The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In some embodiments, an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. 
     The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. 
     As used herein, the terms “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in this context in reference to a ring atom, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or  + NR (as in N-substituted pyrrolidinyl). 
     A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. 
     As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. 
     As described herein, compounds of the invention may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. 
     Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH 2 ) 0-4 R ◯ ; —(CH 2 ) 0-4 OR ◯ ; —O(CH 2 ) 0-4 R ◯ , —O—(CH 2 ) 0-4 C(O)OR ◯ ; —(CH 2 ) 0-4 CH(OR ◯ ) 2 ; —(CH 2 ) 0-4 SR ◯ ; —(CH 2 ) 0-4 Ph, which may be substituted with R ◯ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R ◯ ; —CH═CHPh, which may be substituted with R ◯ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R ◯ ; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-4 N(R ◯ ) 2 ; —(CH 2 ) 0-4 N(R ◯ )C(O)R ◯ ; —N(R ◯ —)C(S)R ◯ ; —(CH 2 ) 0-4 N(R ◯ )C(O)NR ◯   2 ; —N(R ◯ )C(S)NR ◯   2 ; —(CH 2 ) 0-4 N(R ◯ )C(O)OR ◯ ; —N(R ◯ )N(R ◯ )C(O)R ◯ ; —N(R ◯ )N(R ◯ )C(O)NR ◯   2 ; —N(R ◯ )N(R ◯ )C(O)OR ◯ ; —(CH 2 ) 0-4 C(O)R ◯ ; —C(S)R ◯ ; —(CH 2 ) 0-4 C(O)OR ◯ ; —(CH 2 ) 0-4 C(O)SR ◯ ; —(CH 2 ) 0-4 C(O)OSiR ◯   3 ; —(CH 2 ) 0-4 OC(O)R ◯ ; —OC(O)(CH 2 ) 0-4 SR—, SC(S)SR ◯ ; —(CH 2 ) 0-4 SC(O)R ◯ ; —(CH 2 ) 0-4 C(O)NR ◯   2 ; —C(S)NR ◯   2 ; —C(S)SR ◯ ; —SC(S)SR ◯ , —(CH 2 ) 0-4 OC(O)NR ◯   2 ; —C(O)N(OR ◯ )R ◯ ; —C(O)C(O)R ◯ ; —C(O)CH 2 C(O)R ◯ ; —C(NOR ◯ )R ◯ ; —(CH 2 ) 0-4 SSR ◯ ; —(CH 2 ) 0-4 S(O) 2 R ◯ ; —(CH 2 ) 0-4 S(O) 2 OR ◯ ; —(CH 2 ) 0-4 OS(O) 2 R ◯ ; —S(O) 2 NR ◯   2 ; —(CH 2 ) 0-4 S(O)R ◯ ; —N(R ◯ )S(O) 2 NR ◯   2 ; —N(R ◯ )S(O) 2 R ◯ ; —N(OR ◯ )R ◯ ; —C(NH)NR ◯   2 ; —P(O) 2 R ◯ ; —P(O)R ◯   2 ; —OP(O)R ◯   2 ; —OP(O)(OR ◯ ) 2 ; SiR ◯   3 ; —(C 1-4  straight or branched alkylene)O—N(R ◯ ) 2 ; or —(C 1-4  straight or branched alkylene)C(O)O—N(R ◯ ) 2 , wherein each R ◯  may be substituted as defined below and is independently hydrogen, C 1-6  aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, —CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ◯ , taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. 
     Suitable monovalent substituents on R ◯  (or the ring formed by taking two independent occurrences of R ◯  together with their intervening atoms), are independently halogen, —(CH 2 ) 0-2 R ● , -(haloR ● ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ● , —(CH 2 ) 0-2 CH(OR ● ) 2 ; —O(haloR ● ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ● , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ● , —(CH 2 ) 0-2 SR ● , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NR ●   2 , —NO 2 , SiR ●   3 , —C(O)SR ●   3 , —(C 1-4  straight or branched alkylene)C(O)OR ● , or —SSR ●  wherein each R ●  is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1-4  aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ◯  include ═O and ═S. 
     Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) 2 R*, ═NR*, ═NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C iv, aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6  aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     Suitable substituents on the aliphatic group of R* include halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ●   2 , or —NO 2 , wherein each R ●  is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4  aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R † , —NR †   2 , —C(O)R † , —C(O)OR † , —C(O)C(O)R † , —C(O)CH 2 C(O)R † , —S(O) 2 R † , —S(O) 2 NR †   2 , —C(S)NR †   2 , —C(NH)NR †   2 , or —N(R † )S(O) 2 R † ; wherein each R †  is independently hydrogen, C 1-6  aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R † , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     Suitable substituents on the aliphatic group of R †  are independently halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ●   2 , or —NO 2 , wherein each R ●  is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4  aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. 
     In certain embodiments, the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. 
     Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a  13 C- or  14 C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. 
     The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom, thereby forming a carbonyl. 
     DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 
     Prostate Cancer 
     Prostate cancer is the second most common cause of cancer death in men in the United States, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men, who develop recurrent disease that is usually manifest first as a rise in plasma prostate-specific antigen (PSA) followed by spread to distant sites. 
     Castration Therapy 
     Prostate cancer cells are known to depend on androgen receptor (AR) for their proliferation and survival. As such, prostate cancer patients are physically castrated or chemically castrated by treatment with agents that block production of testosterone (e.g. GnRH agonists), alone or in combination with antiandrogens, which antagonize effects of any residual testosterone. This approach is effective as evidenced by a drop in PSA and regression of any visible tumor. 
     Anti-androgens are useful for the treatment of prostate cancer during its early stages. However, prostate cancer often advances to a hormone-refractory state in which the disease progresses despite continued androgen ablation or anti-androgen therapy. Antiandrogens include but are not limited to flutamide, nilutamide, bicalutamide, and/or megestrol. 
     Castration Resistant Prostate Cancer 
     This hormone-refractory state to which most patients eventually progresses in the presence of continued androgen ablation or anti-androgen therapy is known as “castration resistant” prostate cancer (CRPC). 
     CRPC is associated with an overexpression of AR. Compelling data demonstrates that AR is expressed in most prostate cancer cells and overexpression of AR is necessary and sufficient for androgen-independent growth of prostate cancer cells. Failure in hormonal therapy, resulting from development of androgen-independent growth, is an obstacle for successful management of advanced prostate cancer. 
     Advances in Prostate Cancer Treatment 
     Interestingly, while a small minority of CRPC does bypass the requirement for AR signaling, the vast majority of CRPC, though frequently termed “androgen independent prostate cancer” or “hormone refractory prostate cancer,” retains its lineage dependence on AR signaling. 
     Recently, more effective second generation antiandrogens have been developed. These include but are not limited to ARN-509 and enzalutamide, which are thought to function both by inhibiting AR nuclear translocation and DNA binding. 
     Doubly Resistant Prostate Cancer 
     Recently approved therapies that target androgen receptor (AR) signaling such as abiraterone and enzalutamide have transformed clinical management of CRPC. Despite these successes, sustained response with these agents is limited by acquired resistance which typically develops within ˜6-12 months. Doubly resistant prostate cancer is characterized in that tumor cells have become castration resistant and overexpress AR, a hallmark of CRPC. However, cells remain resistant when treated with second generation antiandrogens. 
     In some embodiments doubly resistant prostate cancer cells are characterized by a lack of effectiveness of second generation antiandrogens in inhibiting tumor growth. In some embodiments doubly resistant prostate cancer cells are characterized in that tumor volume increases by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more in the presence of second generation antiandrogens relative to a historical level. 
     In some embodiments, doubly resistant prostate cancer cells are characterized in that tumor volume increases after 1, 2, 3, 4, 5, 6, or 7 days or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 weeks of Androgen Receptor inhibitor therapy. 
     In some embodiments, Androgen Receptor inhibitor therapy comprises treatment with 0.001, 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 5, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000, 10,000, 100,000 mg/kg ARN-509 or enzalutamide administered 1, 2, 3, 4, or 5 times daily, once every other day, once every 2, 3, 4, 5 or 6 days, or once a week. In some embodiments, treatment with second generation antiandrogens comprises treatment with 10 mg/kg ARN-509 or enzalutamide daily. 
     Androgen Receptor 
     The androgen receptor (AR), located on Xql 1-12, is a 110 kD nuclear receptor that, upon activation by androgens, mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. Similar to other steroid receptors, unbound AR is mainly located in cytoplasm and associated with a complex of heat shock proteins (HSPs) through interactions with its ligand-binding domain. Upon agonist binding, AR undergoes a series of conformational changes: heat shock proteins dissociate from AR, and transformed AR undergoes dimerization, phosphorylation, and nuclear translocation, which is mediated by its nuclear localization signal. Translocated receptor then binds to androgen response elements (ARE), which are characterized by a six-nucleotide half-site consensus sequence 5′-TGTTCT-3′ spaced by three random nucleotides and are located in promoter or enhancer regions of AR gene targets. Recruitment of other transcription co-regulators (including co-activators and co-repressors) and transcriptional machinery further ensures transactivation of AR-regulated gene expression. All of these processes are initiated by ligand-induced conformational changes in the ligand-binding domain. 
     AR signaling is crucial for development and maintenance of male reproductive organs including prostate glands, as genetic males harboring loss of function AR mutations and mice engineered with AR defects do not develop prostates or prostate cancer. This dependence of prostate cells on AR signaling continues even upon neoplastic transformation. 
     AR has been purified, characterized, cloned and sequenced from both mouse and human sources. The AR protein contains 920 amino acid residues. Exemplary amino acid and nucleotide sequences from a full-length human AR polypeptide are shown below as SEQ IDs NO: 1 and 2. In some embodiments, an AR polypeptide includes at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of a AR polypeptide sequence, e.g., at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of the sequence shown in SEQ ID NO: 1 or of a sequence at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) identical to SEQ ID NO: 1. In some embodiments, an AR polypeptide comprises an amino acid sequence that is at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) identical to at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of the sequence shown in SEQ ID NO: 1. In some embodiments, an AR polypeptide is a full-length AR polypeptide (e.g., the polypeptide comprises the amino acid sequence of SEQ ID NO: 1). 
     Glucocorticoid Receptor 
     In some embodiments, the present invention encompasses the recognition that increased signaling through the glucocorticoid receptor can compensate for inhibition of androgen receptor signaling in castration resistant prostate cancer and doubly resistant prostate cancer. That is, CRPC occurs when cells overexpress AR. When those cells are then treated with second generation antiandrogens, AR target gene expression is inhibited. Doubly resistant prostate cancer develops when expression of a subset of those target genes is restored, indicating that a transcription factor other than AR is responsible for the target gene activation. 
     The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFκ-B. Such interactions result in inhibition of API- and NFκ-B-mediated transcription and are believed to be responsible for some of the anti-inflammatory activity of exogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU-486 is an example of a non-selective glucocorticoid receptor antagonist. 
     Exemplary amino acid and nucleotide sequences from a full-length human GR polypeptide are shown below as SEQ ID NOs: 3-21. In some embodiments, a GR polypeptide includes at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of a GR polypeptide sequence as set forth in one or more of SEQ ID NOs: 3-21, e.g., at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of the sequence shown in any of SEQ ID NOs: 3-13 or of a sequence at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) identical to one or more of SEQ ID NOs: 3-13. In some embodiments, a GR polypeptide comprises an amino acid sequence that is at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) identical to at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, or 400 consecutive amino acids of the sequence shown in one or more of SEQ ID NOs: 3-13. 
     In some embodiments, GR transcription is activated in patients susceptible to or suffering from CRPC or Doubly Resistant Prostate Cancer relative to a reference. In some embodiments, transcription of GR is activated 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 10,000 fold or more. 
     In some embodiments, transcriptional activation of GR is detected by determining a level of GR mRNA transcripts. Methods of detecting and/or quantifying levels of mRNA transcripts are well known in the art and include but are not limited to northern analysis, semi-quantitative reverse transcriptase PCR, quantitative reverse transcriptase PCR, and microarray analysis. These and other basic RNA transcript detection procedures are described in Ausebel et al. (Ausubel F M, Brent R, Kingston R E, Moore D D, Seidman J G, Smith J A, Struhl K (eds). 1998 . Current Protocols in Molecular Biology . Wiley: New York). 
     In some embodiments, transcriptional activation of GR is detected by determining a level of GR protein. Methods of detecting and/or quantifying protein levels are well known in the art and include but are not limited to western analysis and mass spectrometry. These and all other basic protein detection procedures are described in Ausebel et al. (Ausubel F M, Brent R, Kingston R E, Moore D D, Seidman J G, Smith J A, Struhl K (eds). 1998 . Current Protocols in Molecular Biology . Wiley: New York). 
     In some embodiments, a reference is a sample from an individual without CRPC. In some embodiments, a reference is a sample from an individual without Doubly Resistant Prostate Cancer. In some embodiments, a reference is a sample from an individual without prostate cancer. 
     Inhibitors (i.e., Inhibitor Agents) 
     In some embodiments, the present invention encompasses the recognition that inhibition of GR comprises an effective treatment for CRPC and/or doubly resistant prostate cancer. 
     In some embodiments, an inhibitor for use in accordance with the present invention is or comprises a GR inhibitor. In some embodiments, an inhibitor for use in accordance with the present invention is or comprises a GR and/or an AR inhibitor. In some embodiments, an inhibitor for use in accordance with the present invention is or comprises an AR inhibitor. In some embodiments, an inhibitor for use in accordance with the present invention inhibits SGK1, GR and/or AR level and/or activity. In some embodiments, such level refers to level of SGK1, GR and/or AR mRNA. In some embodiments, such level refers to level of SGK1, GR and/or AR protein, such level refers to level of particular form (e.g., three-dimensional folded form or complex, post-transcriptionally modified form, etc) of SGK1, GR and/or AR protein. In some embodiments, levels comprise levels of a particular form of SGK1, GR and/or AR protein. In some embodiments, a particular form of GR and/or AR protein comprises an active form. In some embodiments, a particular form of SGK1, GR and/or AR protein is or comprises a phosphorylated form. In some embodiments, a particular form of SGK1, GR and/or AR protein is or comprises a glycosylated form. In some embodiments, a particular form of SGK1, GR and/or AR protein is or comprises a sulfylated form. In some embodiments, a particular form of SGK1, GR and/or AR protein is or comprises an enzymatically cleaved form. 
     In some embodiments, an inhibitor (e.g., an SGK1, GR, and/or AR inhibitor) is an inhibitory agent characterized in that, when the agent is contacted with a system expressing or capable of expressing active target (e.g., active SGK1, GR, and/or AR), level and/or activity of the target in the system is reduced (in the absolute and/or relative to level and/or activity of a reference entity, which reference entity in some embodiments may be or comprise a different form of the same target) in its presence compared with a reference level or activity observed under otherwise comparable conditions when the agent is absent or is present at a lower level. 
     In some embodiments, detection, assessment, and/or characterization of an inhibitor includes determination of a reference target level or activity (e.g., that observed under otherwise comparable conditions in absence of the inhibitor) is determined. In some embodiments such a reference target level or activity is determined concurrently with an inhibited target level or activity (i.e., a level or activity of the target when the inhibitor is present at a particular level; in some embodiments at more than one levels. In some embodiments, a reference level or activity is determined historically relative to determination of the inhibited level or activity. In some embodiments, a reference level or activity is or comprises that observed in a particular system, or in a comparable system, under comparable conditions lacking the inhibitor. In some embodiments, a reference level or activity is or comprises that observed in a particular system, or a comparable system, under otherwise identical conditions lacking the inhibitor. 
     In some embodiments, detection, assessment, and/or characterization of an inhibitor includes determination of a control entity level or activity (e.g., a level or activity of a control entity observed when the inhibitor is present). In some embodiments, the control is an entity other than the inhibitor&#39;s target. In some embodiments, the control entity is a form of the target different from the relevant inhibited form. In some embodiments, such a control entity level or activity is determined concurrently with an inhibited target level or activity (i.e., a level or activity of the target when the inhibitor is present at a particular level; in some embodiments at more than one levels). In some embodiments, a control entity level or activity is determined historically relative to determination of the inhibited level or activity. In some embodiments, a control entity level or activity is or comprises that observed in a particular system, or in a comparable system, under comparable conditions including presence of the inhibitor. In some embodiments, a control entity level or activity is or comprises that observed in a particular system, or a comparable system, under identical conditions including presence of the inhibitor. 
     In some embodiments, inhibitor is characterized in that RNA level is lower in a relevant expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, GR mRNA level is reduced 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000% or more relative to a reference level or to an appropriate control. 
     In some embodiments, a GR inhibitor is characterized in that GR protein level is lower in a relevant expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, GR protein level is reduced 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000% or more relative to a reference level or to an appropriate control. 
     In some embodiments, a GR inhibitor inhibits GR activity. In some embodiments, a GR inhibitor inhibits GR transcriptional activation activity. Any of a variety of assays can be used to assess GR transcriptional activation activity. Techniques well known in the art include direct binding assays and competition assays. In some embodiments, GR activity is assessed by mRNA levels of genes regulated by GR. 
     Genes regulated by GR include but are not limited to ABHD2, ACTA2, ATAD2, AZGP1, BCL6, C10RF149, C60RF85, C70RF63, C90RF152, CEBPD, CGNL1, CHKA, CRY2, DBC1, DDIT4, EEF2K, EMP1, ERRFI1, FKBP5, FLJ22795, FOX03, GADD45B, GHR, HERC5, HOMER2, HSD11B2, KBTBD11, KIAA0040, KLF15, KLF9, KRT80, LIN7B, LOC100130886, LOC100131392, LOC100134006, LOC340970, LOC399939, LOC440040, LOC728431, MEAF6, MT1X, NPC1, NRP1, PGC, PGLYRP2, PHLDA1, PNLIP, PPAP2A, PRKCD, PRR15L, RGS2, RHOB, S100P, SCNN1G, SGK, SGK1, SLC25A18, SPRYD5, SPSB1, STK39, TRIM48, TUB A3 C, TUBA3D, TUB A3E, ZBTB16, ZMIZ1, and ZNF812. 
     In some embodiments, a GR inhibitor is characterized in that level of a particular form of lower in a relevant expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, level of the relevant GR form is reduced 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000% or more relative to a reference level or to an appropriate control. 
     In some embodiments a reference GR level or activity is determined. In some embodiments a reference GR level or activity is determined concurrently with the determined GR level or activity. In some embodiments, a reference GR level or activity is or comprises that observed in the system or a comparable system under comparable conditions lacking the GR inhibitor. In some embodiments, a reference GR level or activity comprises the GR level or activity that is observed in the system or a comparable system under otherwise identical conditions lacking the GR inhibitor. 
     In some embodiments, a reference GR level or activity comprises the GR level or activity that is observed in the system or a comparable system under comparable conditions that includes presence of a positive control agent. In some embodiments, a positive control agent comprises an agent characterized in that level or activity of SGK1 activation is higher in an SGK1 expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. 
     In some embodiments, a reference GR level or activity comprises the SGK1 activation level or activity that is observed in the system or a comparable system under comparable conditions that include presence of a negative control agent. In some embodiments, a negative control agent comprises an agent characterized in that level or activity of GR is lower in a GR expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. 
     In some embodiments, a GR inhibitor is characterized in that it reduces tumor volume by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more. 
     In some embodiments, a GR inhibitor is characterized in that it reduces tumor volume by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more. 
     In some embodiments, the present invention encompasses the recognition that inhibition of GR in conjunction with inhibition of AR comprises an effective treatment for CRPC and/or doubly resistant prostate cancer. 
     In some embodiments, inhibitor does not significantly activate AR. In some embodiments, a GR inhibitor is an AR inhibitor. In some embodiments, a GR inhibitor is not an AR inhibitor. 
     In some embodiments, an AR inhibitor is an inhibitory agent characterized in that, when the agent is contacted with a system expressing or capable of expressing Androgen Receptor, level and/or activity of Androgen Receptor in the system is reduced in its presence compared with a reference level or activity observed under otherwise comparable conditions when the agent is absent or is present at a lower level. 
     In some embodiments, an AR inhibitor is characterized in that a Androgen Receptor mRNA level is lower in a relevant Androgen Receptor expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. In some embodiments, an Androgen Receptor mRNA level is reduced 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000% or more relative to a reference level. 
     In some embodiments, an AR inhibitor inhibits AR activity. In some embodiments, an AR inhibitor inhibits AR transcriptional activation activity. Any of a variety of assays can be used to assess AR transcriptional activation activity. Techniques well known in the art include direct binding assays and competition assays. In some embodiments, AR activity is assessed by mRNA levels of genes regulated by AR. Genes regulated by AR include but are not limited to ABHD2, ACTA2, ATAD2, AZGP1, BCL6, C10RF149, C60RF85, C70RF63, C90RF152, CEBPD, CGNL1, CHKA, CRY2, DBC1, DDIT4, EEF2K, EMP1, ERRFI1, FKBP5, FLJ22795, FOX03, GADD45B, GHR, HERC5, HOMER2, HSD11B2, KBTBD11, KIAA0040, KLF15, KLF9, KRT80, LIN7B, LOC100130886, LOC100131392, LOC100134006, LOC340970, LOC399939, LOC440040, LOC728431, MEAF6, MT1X, NPC1, NRP1, PGC, PGLYRP2, PHLDA1, PNLIP, PPAP2A, PRKCD, PRR15L, RGS2, RHOB, S100P, SCNN1G, SGK, SGK1, SLC25A18, SPRYD5, SPSB1, STK39, TRIM48, TUB A3 C, TUBA3D, TUBA3E, ZBTB16, ZMIZ1, and ZNF812. In some embodiments, a mRNA level of a gene regulated by AR is reduced 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1000% or more relative to a reference level. 
     In some embodiments a reference AR level or activity is determined. In some embodiments a reference AR level or activity is determined concurrently with the determined AR level or activity. In some embodiments, a reference AR level or activity is determined historically relative to the determined AR level or activity. In some embodiments, a reference AR level or activity comprises an AR level or activity that is observed in the system or a comparable system under comparable conditions lacking the AR inhibitor. In some embodiments, a reference AR level or activity comprises the AR level or activity that is observed in the system or a comparable system under otherwise identical conditions lacking the AR inhibitor. 
     In some embodiments, a reference AR level or activity comprises the AR level or activity that is observed in the system or a comparable system under comparable conditions that includes presence of a positive control agent. In some embodiments, a positive control agent comprises an agent characterized in that level or activity of AR activation is higher in a AR expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. 
     In some embodiments, a reference AR level or activity comprises the AR activation level or activity that is observed in the system or a comparable system under comparable conditions that include presence of a negative control agent. In some embodiments, a negative control agent comprises an agent characterized in that level or activity of AR is lower in a AR expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. 
     In some embodiments, an AR inhibitor is characterized in that it reduces tumor volume by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more. 
     As described herein, GR inhibitors, and AR inhibitors for use in accordance with the present invention are inhibitory agents and can be of any class of chemical compounds, including for example a class of chemical compounds selected from the group consisting of macromolecules (e.g. polypeptides, protein complexes, nucleic acids, lipids, carbohydrates, etc) and small molecules (e.g., amino acids, nucleotides, organic small molecules, inorganic small molecules, etc). Particular examples of protein macromolecules are proteins, protein complexes, and glycoproteins, for example such as antibodies or antibody fragments. Particular examples of nucleic acid macromolecules include DNA, RNA (e.g., siRNA, shRNA), and PNA (peptide nucleic acids). In some embodiments, nucleic acid macromolecules are partially or wholly single stranded; in some embodiments they are partially or wholly double stranded, triple stranded, or more. Particular examples of carbohydrate macromolecules include polysaccharides. Particular examples of lipid macromolecules include esters of fatty acids (e.g. triesters such as triglycerides), phospholipids, eicosanoids (e.g., prostaglandins), etc. Examples of small molecules include peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, oligonucleotides, nucleotides, nucleotide analogs, terpenes, steroids, vitamins and inorganic compounds e.g., heteroorganic or organometallic compounds. 
     In some embodiments, an AR inhibitor is or comprises a small molecule. 
     In some embodiments, Ritor will have a formula weight of less than about 10,000 grams per mole, less than 5,000 grams per mole, less than 1,000 grams per mole, or less than about 500 grams per mole, e.g., between 5,000 to 500 grams per mole. 
     In some embodiments, a GR inhibitor is selected from the group consisting of RU-486 and analogs thereof. In some embodiments, a GR inhibitor is selected from the group consisting of ORG 34517, 
     
       
         
         
             
             
         
       
     
     and analogs thereof. 
     In some embodiments, an AR inhibitor is selected from the group consisting of 3,3′-diindolylmethane (DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide, finasteride, flutamide, izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidal antiandrogens, turosteride, and analogs and combinations thereof. 
     In some embodiments, an AR inhibitor is selected from the group consisting of ARN-509 and analogs thereof and/or enzalutamide and analogs thereof. In some embodiments, an AR inhibitor is or comprises ARN-509. In some embodiments, an AR inhibitor is or comprises enzalutamide. 
     In some embodiments, the present invention provides a compound of formula I′ 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
         each R 1  is independently selected from halogen, optionally substituted C 1-6 aliphatic, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(R) 3 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R)2, SO 2 N(R) 2 , OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, and OC(O)N(R) 2 ; or two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 5- to 7-membered ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur;   R 2  is optionally substituted unsaturated C 2-6 aliphatic;   each R is independently hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 8- to 10-membered bicyclic aryl; and   n is from 0-4.       

     In certain embodiments, n is 1-3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. 
     In some embodiments, each R 1  is independently selected from optionally substituted C 1-6 aliphatic, —OR, —SR, or —N(R) 2 . In some embodiments, each R 1  is independently —OR, —SR, or —N(R) 2 , wherein each R is independently an optionally substituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, 8- to 10-membered bicyclic aryl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. 
     In some embodiments, R 1  is —OR, —SR, —N(R) 2 , —S(O)R, —S(O) 2 R, or —C(R) 3 , and R is optionally substituted phenyl. 
     In some embodiments, R 1  is —OR, —SR, —N(R) 2 , or —C(R) 3 , and R is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl ring. 
     In some embodiments, R 1  is —OR, —SR, —N(R) 2 , —S(O)R, —S(O) 2 R, or —C(R) 3 , and R is an optionally substituted 5-membered heteroaryl having 1 heteroatom selected from oxygen, nitrogen, or sulfur. 
     In some embodiments, R 1  is —OR, —SR, —N(R) 2 , —S(O)R, —S(O) 2 R, or —C(R) 3 , and R is an optionally substituted 6-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. 
     In some embodiments, each R 1  is optionally substituted C 1-6 aliphatic. In some embodiments, R 1  is C 1 alkyl-C 3-7 cycloalkyl, C 1 alkyl-heteroaryl, or C 1 alkyl-aryl, wherein the aryl groups is selected from phenyl or 8- to 10-membered bicyclic aryl, and the heteroaryl group selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, or 7- to 10-membered saturated or partially unsaturated bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. 
     In some embodiments, two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 5- to 7-membered ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 5-membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 6-membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur. 
     In some embodiments, R 2  is optionally substituted unsaturated C 2-4 aliphatic. In some embodiments, R 2  is unsaturated C 2-6 aliphatic. In some embodiments, R 2  is unsaturated C 2 -5aliphatic. In some embodiments, R 2  is unsaturated C 2-4 aliphatic. In some embodiments, R 2  is unsaturated C 2-3 aliphatic. In some embodiments, R 2  is selected from the group consisting of ethyn-1-yl, 1-propyn-1-yl, 1-butyn-1-yl, ethen-1-yl, 1-propen-1-yl, and 1-buten-1-yl. 
     In some embodiments, R is selected from methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl. 
     In some embodiments, the present invention provides a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , and n is as defined above and described in classes and subclasses herein. 
     In some embodiments, the present invention provides a compound of formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 2  is as defined above and described in classes and subclasses herein, both singly and in combination, and R s  when present is a suitable monovalent substituent as defined above and described in classes and subclasses herein, both singly and in combination. 
     In some embodiments, R s  is selected from —OH, —NH 2 , —CH 3 , —Br, —Cl, —F, —I, —SH, —SOR ◯ , —SO 2 R ◯ , —O—C 1-6 alkyl, —N(R ◯ ) 2 , —S—C 1-6 alkyl, and —C(R ◯ ) 2 -C 1-6 alkyl. In some embodiments, each R ◯  is independently hydrogen or C 1-6 alkyl. 
     In some embodiments, the present invention provides a compound of formula II-a: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R s , when present, is a suitable monovalent substituent on a substitutable carbon as defined above and described in classes and subclasses herein, both singly and in combination. 
     In some embodiments, two R 1  groups on adjacent atoms are taken together with their intervening atoms to form an optionally substituted fused 5-membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, the present invention provides a compound of formula III: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein m is 1-8 and R s , when present, and R 2  are as defined above and described in classes and subclasses herein, both singly and in combination. In some embodiments, R s  is selected from C 1-6 alkyl, —OH, —NH 2 , CH 3 , halogen, —O-aryl, —NR ◯ -aryl, —S-aryl, —O—C 3-7 cycloalkyl, —NR ◯ —C 3-7 cycloalkyl, —S—C 3-7 cycloalkyl, —C(R ◯ ) 2 —C 3-7 cycloalkyl, —OC 1-6 alkyl, —N(R ◯ )C 1-6 alkyl, —S—C 1-6 alkyl, and —C(R ◯ ) 2 -aryl. 
     In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. 
     In some embodiments, the present invention provides a compound of formula III-a: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein m is 1-8. 
     In some embodiments, the present invention provides a compound of formula IV: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein m is 1-8, X is —O—, —S—, —S(O)—, —S(O) 2 —, —NR—, or —C(R ◯ ) 2 -, and R s , when present, R 2  and R ◯  are as defined above and described in classes and subclasses herein, both singly and in combination. In certain embodiments, X is selected from —O—, —S—, —NR—, or —C(R ◯ ) 2 -. 
     In some embodiments, the present invention provides a compound of formula V: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein m′ is 1-8, and each of R s , when present, X, and R 2  is as defined above and described in classes and subclasses herein, both singly and in combination. In some embodiments, R s  is selected from C 1-6 alkyl, —O-aryl, —NR ◯ -aryl, —S-aryl, —O—C 3-7 cycloalkyl, —NR ◯ —C 3-7 cycloalkyl, —S—C 3-7 cycloalkyl, —C(R ◯ ) 2 —C 3-7 cycloalkyl, —OC 1-6 alkyl, —N(R ◯ )C 1-6 alkyl, —S—C 1-6 alkyl, and —C(R ◯ ) 2 -aryl. In some embodiments, each R ◯  is independently hydrogen or C 1-6 alkyl. 
     In some embodiments, the present invention provides a compound of formula VI: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein Y is —O—, —NR s —, —NH—, or —S—, and each of R s , when present, X, and R 2  is as defined above and described in classes and subclasses herein, both singly and in combination. 
     In some embodiments, the present invention provides a compound of formula VII: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 2a  is unsaturated C 2-6 aliphatic, acetyl, guanidinyl, or cyano. In some embodiments, R 2a  is selected from the group consisting of ethyn-1-yl, 1-propyn-1-yl, 1-butyn-1-yl, ethen-1-yl, 1-propen-1-yl, and 1-buten-1-yl. 
     In some embodiments, the present invention provides a compound of formula VIII: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1  is —OR or both R 1  groups are taken together with their intervening atoms to form an optionally substituted fused 5- to 7-membered ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur, and each of R and R 2  is as defined above and described in classes and subclasses herein, both singly and in combination. In some embodiments, the bridge formed by two R 1  groups taken together is selected from —OCH 2 O—, —OCH 2 CH 2 O—, —OC(O)O—, and —OCOCH 2 O—. 
     In some embodiments, a provided compound is: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In some embodiments, a provided compound is: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof. 
     In certain embodiments a provided compound is selected from the following, or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, a provided compound is other than the compounds depicted in  FIG. 8 . 
     In certain embodiments, compounds of formula I′, I, II, II-a, III, III-a, IV, V, VI, VII, and VIII, and compounds I-1 through I-10, are useful in each of the methods described herein. 
     Synthesis of Compounds 
     Compounds of the invention are synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention. 
     In certain embodiments, the present compounds are generally prepared according to Scheme A set forth below: 
     
       
         
         
             
             
         
       
     
     Compounds of the invention may also be made according to the methods described by Prat et al., Tet. Lett. 45 (2004), 765-768; Prat et al., Org. Proc. Res. &amp; Dev. (2004), 5, 219-228; Napolitano et al., Gazzetta Chimica Italiana 120 (1990), 323-326; Teutsch et al., Tet. Lett. 22 (1979), 2051-2054; US Patent Publication Nos. 2004224933 and 2004229853 and French Patent Application Publication No. 2,201,287, the entire contents of each of which are hereby incorporated by reference herein. 
     In some embodiments, “ABR173” and “ABR208” are used interchangeably, and “ABR167” and “ABR240” are also used interchangeably. 
     Antibodies 
     In some embodiments, an AR inhibitor for use in accordance with the present invention is or comprises an antibody or antigen-binding fragment thereof. In some embodiments, a GR inhibitor is or comprises an antibody or antigen-biding fragment thereof that binds specifically to a GR polypeptide (e.g., to a reference GR as set forth in one or more of SEQ ID NOs 3-13, or to a polypeptide whose amino acid sequence shows at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more overall sequence identity therewith). In some embodiments, an AR inhibitor is or comprises an antibody or antigen-binding fragment thereof that binds to an AR polypeptide (e.g., to a reference AR as set forth in SEQ ID NO: 1, or to a polypeptide whose amino acid sequence shows at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more overall sequence identity therewith). 
     An inhibitory agent as described herein may be or comprise an antibody, or fragment thereof, of any appropriate isotype, including, for example: IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgM, IgA1, IgA2, IgD, or IgE. In some embodiments, an antibody, or fragment thereof, is an IgG isotype, e.g., IgG1 or IgG4. 
     In some embodiments, an inhibitory agent may be or comprise a full-length antibody is full-length. In some embodiments, an inhibitory agent may be or comprise only an antigen-binding fragment (e.g., a Fab, F(ab)2, Fv or single chain Fv fragment) of an antibody (e.g., an may lack or be substantially free of other antibody components). In some embodiments, an inhibitory agent may be or comprise multiple antigen-binding components of an antibody (e.g., as in a diabody or zybody). In some embodiments, an inhibitory agent may include one or more CDRs found in a full-length antibody raised in an organism against the relevant antigen. In some embodiments, an inhibitory agent may include such CDRs in a different polypeptide context than that in which they are found in the organism-raised antibody. 
     In some embodiments, an inhibitory agent may be or comprise an antibody, or fragment thereof, that is monoclonal, recombinant, chimeric, deimmunized, human, humanized, etc as these terms are understood in the art. 
     As is known in the art, monoclonal antibodies can be produced by a variety of techniques, including conventional monoclonal antibody methodology, e.g., the standard somatic cell hybridization technique of Kohler and Milstein, Nature 256: 495, 1975. Polyclonal antibodies can be produced by immunization of animal or human subjects. See generally, Harlow, E. and Lane, D.  Antibodies; A Laboratory Manual , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988. Recombinant, chimeric, deimmunized, human, or humanized antibodies can also be produced using standard techniques, as is known in the art. Techniques for engineering and preparing antibodies are described, for example, in U.S. Pat. No. 4,816,567, issued Mar. 28, 1989; U.S. Pat. No. 5,078,998, issued Jan. 7, 1992; U.S. Pat. No. 5,091,513, issued Feb. 25, 1992; U.S. Pat. No. 5,225,539, issued Jul. 6, 1993; U.S. Pat. No. 5,585,089, issued Dec. 17, 1996; U.S. Pat. No. 5,693,761, issued Dec. 2, 1997; U.S. Pat. No. 5,693,762, issued Dec. 2, 1997; U.S. Pat. No. 5,869,619; issued 1991; U.S. Pat. No. 6,180,370, issued Jan. 30, 2001; U.S. Pat. No. 6,548,640, issued Apr. 15, 2003; U.S. Pat. No. 6,881,557, issued Apr. 19, 2005; U.S. Pat. No. 6,982,321, issued Jan. 3, 2006; incorporated herein by reference. Antibodies described herein can be used, e.g., for detection (e.g., diagnostic) assays, and/or for therapeutic applications. 
     RNAi 
     In some embodiments, a GR inhibitor or an AR inhibitor for use in accordance with the present invention inhibits via RNA interference. RNA interference refers to sequence-specific inhibition of gene expression and/or reduction in target RNA levels mediated by an at least partly double-stranded RNA, which RNA comprises a portion that is substantially complementary to a target RNA. Typically, at least part of the substantially complementary portion is within the double stranded region of the RNA. In some embodiments, RNAi can occur via selective intracellular degradation of RNA. In some embodiments, RNAi can occur by translational repression. In some embodiments, RNAi agents mediate inhibition of gene expression by causing degradation of target transcripts. In some embodiments, RNAi agents mediate inhibition of gene expression by inhibiting translation of target transcripts. In some embodiments, RNAi agent includes a portion that is substantially complementary to a target RNA. In some embodiments, RNAi agents are at least partly double-stranded. In some embodiments, RNAi agents are single-stranded. In some embodiments, exemplary RNAi agents can include small interfering RNA (siRNA), short hairpin RNA (shRNA), and/or microRNA (miRNA). In some embodiments, an agent that mediates RNAi includes a blunt-ended (i.e., without overhangs) dsRNA that can act as a Dicer substrate. For example, such an RNAi agent may comprise a blunt-ended dsRNA which is &gt;25 base pairs length. RNAi mechanisms and the structure of various RNA molecules known to mediate RNAi, e.g. siRNA, shRNA, miRNA and their precursors, are described, e.g., in Dykxhhorn et al., 2003, Nat. Rev. Mol. Cell. Biol., 4:457; Hannon and Rossi, 2004, Nature, 431:3761; and Meister and Tuschl, 2004, Nature, 431:343; all of which are incorporated herein by reference. 
     In some embodiments, a GR inhibitor or an AR inhibitor for use in accordance with the present invention an siRNA or an shRNA. In some embodiments, an inhibitory agent is or comprises a siRNA or shRNA that binds specifically to SGK1 RNA (e.g., to a reference SGK1 as set forth in one or more of SEQ ID NOs 26-29, or to an RNA whose nucleic acid sequence shows at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more overall sequence identity therewith). In some embodiments, the siRNA or an shRNA binds to full length SGK1 RNA. In some embodiments, the siRNA or an shRNA binds to a fragment of SGK1 RNA at least 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or more nucleotides long). In some embodiments, an inhibitory agent is or comprises a siRNA or shRNA that binds specifically to GR RNA (e.g., or shRNA binds specifically to RNA (e.g., to a reference GR as set forth in one or more of SEQ ID NOs 14-21, or to an RNA whose nucleic acid sequence shows at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more overall sequence identity therewith). In some embodiments, the siRNA or an shRNA binds to full length GR RNA. In some embodiments, the siRNA or an shRNA binds to a fragment of GR RNA at least 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or more nucleotides long).). In some embodiments, an inhibitory agent is or comprises a siRNA or shRNA that binds specifically to AR RNA (e.g., to a reference AR as set forth in SEQ ID NO: 2, or to an RNA whose nucleic acid sequence shows at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more overall sequence identity therewith). In some embodiments, the siRNA or an shRNA binds to full length AR RNA. In some embodiments, the siRNA or an shRNA binds to a fragment of AR RNA at least 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or more nucleotides long). In some embodiments, an AR inhibitor is or comprise siRNA that targets AR. In some embodiments, a GR inhibitor is or comprise shRNA that targets GR. In some embodiments, an AR inhibitor is or comprise shRNA that targets AR. Inhibitory nucleic acids are well known in the art. For example, siRNA, shRNA and double-stranded RNA have been described in U.S. Pat. Nos. 6,506,559 and 6,573,099, as well as in U.S. Patent Publications 2003/0051263, 2003/0055020, 2004/0265839, 2002/0168707, 2003/0159161, and 2004/0064842, all of which are herein incorporated by reference in their entirety. 
     RNA interference refers to sequence-specific inhibition of gene expression and/or reduction in target RNA levels mediated by an at least partly double-stranded RNA, which RNA comprises a portion that is substantially complementary to a target RNA. Typically, at least part of the substantially complementary portion is within the double stranded region of the RNA. In some embodiments, RNAi can occur via selective intracellular degradation of RNA. In some embodiments, RNAi can occur by translational repression. In some embodiments, RNAi agents mediate inhibition of gene expression by causing degradation of target transcripts. In some embodiments, RNAi agents mediate inhibition of gene expression by inhibiting translation of target transcripts. Generally, an RNAi agent includes a portion that is substantially complementary to a target RNA. In some embodiments, RNAi agents are at least partly double-stranded. In some embodiments, RNAi agents are single-stranded. In some embodiments, exemplary RNAi agents can include small interfering RNA (siRNA), short hairpin RNA (shRNA), and/or microRNA (miRNA). In some embodiments, an agent that mediates RNAi includes a blunt-ended (i.e., without overhangs) dsRNA that can act as a Dicer substrate. For example, such an RNAi agent may comprise a blunt-ended dsRNA which is &gt;25 base pairs length. RNAi mechanisms and the structure of various RNA molecules known to mediate RNAi, e.g. siRNA, shRNA, miRNA and their precursors, are described, e.g., in Dykxhhorn et al., 2003, Nat. Rev. Mol. Cell. Biol., 4:457; Hannon and Rossi, 2004, Nature, 431:3761; and Meister and Tuschl, 2004, Nature, 431:343; all of which are incorporated herein by reference. 
     An siRNA, shRNA, or antisense oligonucleotide may inhibit the transcription of a gene or prevent the translation of a gene transcript in a cell. In some embodiments, an inhibitory agent comprises a siRNA or shRNA from 16 to 1000 nucleotides long. In some embodiments, an inhibitory agent comprises an siRNA or, shRNA, from 18 to 100 nucleotides long. In certain embodiments, an inhibitory agent comprises a siRNA or shRNA that is an isolated nucleic acid that targets a nucleotide sequence such as the AR coding sequence (SEQ ID NO: 2), the GR coding sequence (SEQ ID NOs: 14-21), or the SGK1 coding sequence (SEQ ID NOs: 26-29). 
     In some embodiments, an siRNA, shRNA or antisense oligonucleotide is specifically hybridizable to an mRNA encoding a GR polypeptide whose amino acid sequence shows at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) overall sequence identity with a GR polypeptide of any of SEQ ID NOs 3-13. In certain embodiments, the siRNA, shRNA, or antisense oligonucleotide is an isolated nucleic acid that targets to a nucleotide sequence encoding polypeptide fragments of GR. In some embodiments, an siRNA, shRNA or antisense oligonucleotide is specifically hybridizable to an mRNA encoding an AR polypeptide whose amino acid sequence shows at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) overall sequence identity with an AR polypeptide of SEQ ID NO 1. In certain embodiments, the siRNA, shRNA, or antisense oligonucleotide is an isolated nucleic acid that targets a nucleotide sequence encoding polypeptide fragments of AR. 
     Expression Systems 
     In some embodiments, a GR inhibitor or an AR inhibitor for use in accordance with the present invention are characterized in that levels of GR and/or AR are reduced in an expression system when the inhibitor is present as compared with a reference level observed under otherwise comparable conditions when it is absent. 
     In some embodiments an expression system is or comprises a GR expression system. In some embodiments a GR expression system is or comprises an expression system in which GR is expressed. In some embodiments an expression system is or comprises an AR expression system. In some embodiments an AR expression system is or comprises an expression system in which AR is expressed. 
     In some embodiments the expression system is or comprises an in vitro expression system. In some embodiments, the expression system is or comprises an in vivo expression system. 
     In some embodiments an expression system is or comprises cells. In some embodiments, cells comprise prokaryotic cells. In some embodiments, cells comprise eukaryotic cells. In some embodiments, cells are human cells. In some embodiments, cells are mouse cells. In some embodiments, cells are tumor cells. In some embodiments, cells are cells from an individual susceptible to, suffering from, or who has previously had prostate cancer. In some embodiments, cells are cells from an individual susceptible to, suffering from, or who has previously had CRPC. In some embodiments, cells are cells from an individual susceptible to, suffering from, or who has previously had doubly resistant prostate cancer. In some embodiments, cells are prostate cancer cells. In some embodiments, cells are obtained from a living organism. In some embodiments, cells are obtained from cell culture. In some embodiments, cells comprise any cell type capable of expressing GR. In some embodiments, cells comprise any cell type capable of expressing AR. In some embodiments, cells comprise any cell type capable of expressing GR and AR. In some embodiments, cells comprise mouse cell lines. In some embodiments, cells comprise human prostate adenocarcinoma cells. In some embodiments, cells comprise LNCaP/AR cells. In some embodiments, cells comprise CWR22PC cells. In some embodiments, cells comprise CV1 cells. In some embodiments, cells comprise VCaP cells. In some embodiments, cells comprise CS1 cells. In some embodiments, cells comprise LREX′ cells. 
     In some embodiments the expression system is or comprises cells in cell culture. Techniques for culturing a wide variety of cell types are well known in the art. See, for example, Current Protocols in Molecular Biology (N.Y., John Wiley &amp; Sons; Davis et al. 1986). In some embodiments, an expression system may comprise cells in cell culture wherein the cells are cultured in cell culture media. In some embodiments, cell culture media utilized in accordance with the present invention is or comprises serum-free cell culture media. In certain embodiments, utilized cell culture media is fully defined synthetic cell culture media. In some embodiments, utilized cell culture media is Roswell Park Memorial Institute medium (RPMI). In certain embodiments, utilized cell culture media is Dulbecco&#39;s Modified Eagle Medium (DMEM). In certain embodiments, utilized cell culture media is Iscove&#39;s Modified Dulbecco&#39;s Medium (IMEM). In certain embodiments, utilized cell culture media is RPMI, Ham&#39;s F-12, or Mammary Epithelial Cell Growth Media (MEGM). In some embodiments, utilized cell culture media comprises additional components including Fetal Bovine Serum (FBS), charcoal-stripped, dextran-treated fetal bovine serum (CSS), Bovine Serum (BS), and/or Glutamine or combinations thereof. In some embodiments, utilized cell culture media are supplemented with an antibiotic to prevent contamination. Useful antibiotics in such circumstances include, for example, penicillin, streptomycin, and/or gentamicin and combinations thereof. Those of skill in the art are familiar with parameters relevant to selection of appropriate cell culture media. 
     In some embodiments the expression system is or comprises tissue. In some embodiments, the tissue is or comprises prostate tissue. In some embodiments, the tissue is or comprises tissue from a tumor. In some embodiments, the tissue is from an individual susceptible to, suffering from, or who has previously had prostate cancer. In some embodiments, the tissue is from an individual susceptible to, suffering from, or who has previously had CRPC. In some embodiments, the tissue is from an individual susceptible to, suffering from, or who has previously had doubly resistant prostate cancer. 
     In some embodiments the expression system is or comprises an organism. In some embodiments, an organism is an animal. In some embodiments, an organism is an insect. In some embodiments, an organism is a fish. In some embodiments, an organism is a frog. In some embodiments, an organism is a chicken. In some embodiments, an organism is a mouse. In some embodiments, an organism is a rabbit. In some embodiments, an organism is a rat. In some embodiments, an organism is a dog. In some embodiments, an organism is a non-human primate. In some embodiments, an organism is a human. 
     In some embodiments the expression system is or comprises allogenic cells within a host organism. In some embodiments, allogenic cells comprise any cells described herein. In some embodiments, a host organism comprises any organism described herein. In some embodiments allogenic cells comprise LNCaP/AR cells and a host organism comprises castrated mice. 
     In some embodiments, an expression system comprises native SGK1, AR and/or GR present in the genome of the cell, tissue, or host organism. In some embodiments, an expression system comprises exogenous SGK1, AR and/or GR DNA for expressing SGK1, AR and/or GR. Polynucleotides (e.g., DNA fragments) encoding an SGK1, AR and/or GR protein for can be generated by any of a variety of procedures. They can be cleaved from larger polynucleotides (e.g., genomic sequences, cDNA, or the like) with appropriate restriction enzymes, which can be selected, for example, on the basis of published sequences of human SGK1, AR and/or GR. mRNA sequences for human SGK1 are shown in SEQ ID NOs: 26-29. The mRNA sequence for human AR is shown in SEQ ID NO: 2. mRNA sequences for human GR are shown in SEQ ID NOs: 14-21. In some embodiments, polynucleotides encoding an SGK1, AR and/or GR protein can be generated by PCR amplification by selecting appropriate primers based on published sequences such as those above. Methods of PCR amplification, including the selection of primers, conditions for amplification, and cloning of the amplified fragments, are known in the art. See, e.g., Innis, M. A. et al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego, Calif., and Wu et al., eds., Recombinant DNA Methodology, 1989, Academic Press, San Diego, Calif. In some embodiments, polynucleotide fragments encoding an SGK1, AR and/or GR protein can be generated by chemical synthesis. Combinations of the above recombinant or non-recombinant methods, or other conventional methods, can also be employed. 
     In some embodiments, an expression system comprises exogenous AR and/or GR DNA for expressing AR and/or GR contained within an expression vector. An isolated polynucleotide encoding AR and/or GR protein or a fragment thereof can be cloned into any of a variety of expression vectors, under the control of a variety of regulatory elements, and expressed in a variety of cell types and hosts, described herein. 
     Various types of vectors are suitable for expression of AR and/or GR polypeptides in an expression system described herein. The term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include, for example, a plasmid, cosmid or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors include, e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses. Other types of viral vectors are known in the art. 
     In some embodiments, an expression vector is or comprises any vector suitable for containing a nucleic acid encoding an AR and/or GR polypeptide in a form suitable for expression of the nucleic acid encoding an AR and/or GR polypeptide in a host cell. In some embodiments, an expression vector includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. In some embodiments, regulatory sequences are or comprise promoters, enhancers and/or other expression control elements (e.g., polyadenylation signals). In some embodiments, regulatory sequences are or comprise native regulatory sequences. In some embodiments, regulatory sequences are or comprise those which direct constitutive expression of a nucleotide sequence. In some embodiments, regulatory sequences are or comprise tissue-specific regulatory sequences. In some embodiments, regulatory sequences are or comprise inducible sequences. The design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, and the like. 
     In some embodiments, a GR or AR expression system comprises recombinant expression vectors designed for expression of and/or GR polypeptides in prokaryotic cells. In some embodiments, a GR or AR expression system comprises recombinant expression vectors designed for expression of SGK1, AR and/or GR polypeptides in eukaryotic cells. For example, polypeptides can be expressed in  E. coli , insect cells (e.g., using baculovirus expression vectors), yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel,  Gene Expression Technology; Methods in Enzymology  185, Academic Press, San Diego, Calif., 1990. In some embodiments, a GR or AR expression system comprises recombinant expression vectors designed for expression of S AR and/or GR polypeptides in vitro. For example, a recombinant expression vector can be transcribed and translated in vitro using T7 promoter regulatory sequences and T7 polymerase. 
     Techniques for introducing vector DNA into host cells via conventional transformation or transfection techniques are well known in the art. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including, for example, calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, gene gun, or electroporation. 
     Uses 
     Test Agents 
     The present disclosure provides assays for designing, detecting, identifying, and/or characterizing one or more agents to evaluate an effect of the test agent on level or activity of an SGK1, GR and/or AR polypeptide and/or to otherwise assess usefulness as inhibitory agents in accordance with the present invention. 
     Any agent or collection of agents can be designed, detected, identified, characterized and/or otherwise evaluated as a test agent as described herein. For example, any class of inhibitory agents as described above may be so designed, detected, identified, characterized and/or otherwise evaluated. The test agent can be naturally occurring (e.g., a herb or a nature product), synthetic, or both. Examples of macromolecules are proteins (e.g., antibodies, antibody fragments), protein complexes, and glycoproteins, nucleic acids, e.g., DNA, RNA (e.g., siRNA), and PNA (peptide nucleic acid). Examples of small molecules are peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds e.g., heteroorganic or organometallic compounds. 
     In certain embodiments, the test agent is an antibody or antibody fragment (e.g, diabody) directed to GR and/or AR polypeptide. The antibody or antibody fragment may be directed to any region of the GR and/or AR polypeptide. The antibody may be polyclonal or monoclonal. The antibody may be of any isotype. The antibody may be derived from any species; however, for use in humans, the antibody is typically of human origin or has been humanized. If the antibody is to be used in other species, the antibody may be adapted to that species. In certain embodiments, the antibody is a humanized monoclonal antibody. In certain specific embodiments, the antibody is a wholly human monoclonal antibody. 
     In some embodiments, a collection of test agents is provided, and is subjected to one or more assays or assessments as described herein. In some such embodiments, results of such assays or assessments are compared against an appropriate reference so that an inhibitory agent is detected, identified, characterized and/or otherwise evaluated. 
     In some embodiments one or more test agents is designed by chemical modeling. For example, in some embodiments, one or more crystal structures is provided including a binding cleft into which potential inhibitory agent moieties are docked in silico. Alternatively or additionally, in some embodiments, one or more reference chemical structures is provided of compounds or agents that do or do not bind to the target of interest, and structures of one or more test compounds is/are designed with reference to such reference chemical structures, e.g., by preserving interacting moieties and/or modifying or removing non-interacting moieties. In some embodiments, chemical modeling is performed in silico. In some embodiments, chemical modeling is performed using computers, for example that store reference structures and for example permit overlay or other comparison of test structures therewith. In some embodiments, analogs or derivatives of known compounds or agents are designed as described herein, and are optionally prepared and subjected to one or more assays or assessments so that their activity as an inhibitory agent is detected, identified, characterized and/or otherwise evaluated. 
     In some embodiments, test agents may be individually subjected to one or more assays or assessments as described herein. In some embodiments, test agents may be pooled together and then subjected to one or more assays or assessments as described herein. Pools so subjected may then be split for further assays or assessments. 
     In some embodiments, high throughput screening methods are used to screen a chemical or peptide library, or other collection, containing a large number of potential test compounds. Such “chemical libraries” are then screened in one or more assays to identify those library members (particular chemical species or subclasses) that display a desired characteristic activity. Compounds thus identified can serve as conventional “lead compounds” or can themselves be used as potential or actual modulators (e.g., as therapeutics). 
     A chemical compound library typically includes a collection of diverse chemical compounds, for example, generated by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” such as reagents. For example, a linear chemical library such as a polypeptide library may be formed by combining a set of chemical building blocks (amino acids), e.g., in particular specified arrangements or in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can be synthesized through such combinatorial mixing of chemical building blocks. 
     Preparation and screening of libraries of chemical compounds or agents is well known to those of skill in the art. Such libraries include, but are not limited to, peptide libraries (see, e.g., U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991) and Houghton et al., Nature 354:84-88 (1991)). Other chemistries for generating chemical diversity libraries can also be used. Such chemistries include, but are not limited to: peptoids (e.g., PCT Publication No. WO 91/19735), encoded peptides (e.g., PCT Publication No. WO 93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091), benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such as hydantoins, benzodiazepines and dipeptides (Hobbs et al., Proc. Nat. Acad. Sci. USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidal peptidomimetics with glucose scaffolding (Hirschmann et al., J. Amer. Chem. Soc. 114:9217-9218 (1992)), analogous organic syntheses of small compound libraries (Chen et al., J. Amer. Chem. Soc. 116:2661 (1994)), oligocarbamates (Cho et al., Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell et al., J. Org. Chem. 59:658 (1994)), nucleic acid libraries (see Ausubel, Berger and Sambrook, all supra), peptide nucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083), antibody libraries (see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314 (1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang et al., Science, 274:1520-1522 (1996) and U.S. Pat. No. 5,593,853), small organic molecule libraries (see, e.g., benzodiazepines, Baum C&amp;EN, January 18, page 33 (1993); isoprenoids, U.S. Pat. No. 5,569,588; thiazolidinones and metathiazanones, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos. 5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. No. 5,506,337; benzodiazepines, U.S. Pat. No. 5,288,514, and the like). Additional examples of methods for the synthesis or preparation of compound libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and Gallop et al. (1994) J. Med. Chem. 37:1233. 
     Some exemplary libraries are used to generate variants from a particular lead compound. One method includes generating a combinatorial library in which one or more functional groups of the lead compound are varied, e.g., by derivatization. Thus, the combinatorial library can include a class of compounds which have a common structural feature (e.g., scaffold or framework). 
     Devices for the preparation of small molecule libraries (e.g., combinatorial libraries) are commercially available (see, e.g., 357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin, Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus, Millipore, Bedford, Mass.). In addition, numerous small molecule libraries are commercially available (see, e.g., ComGenex, Princeton, N.J., Asinex, Moscow, Ru, Tripos, Inc., St. Louis, Mo., ChemStar, Ltd, Moscow, RU, 3D Pharmaceuticals, Exton, Pa., Martek Biosciences, Columbia, Md., etc.). 
     Test agents can also be obtained from: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann, R. N. et al. (1994) J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the ‘ one-bead one-compound’ library method; synthetic library methods using affinity chromatography selection, or any other source, including assemblage of sets of compounds having a structure and/or suspected activity of interest. Biological libraries include libraries of nucleic acids and libraries of proteins. Some nucleic acid libraries provide, for example, functional RNA and DNA molecules such as nucleic acid aptamers or ribozymes. A peptoid library can be made to include structures similar to a peptide library. (See also Lam (1997) Anticancer Drug Des. 12:145). In certain embodiments, one or more test agents is or comprises a nucleic acid molecule, that mediates RNA interference as described herein. A library of proteins may be produced by an expression library or a display library (e.g., a phage display library). 
     Libraries of test agents may be presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner U.S. Pat. No. 5,223,409), plasmids (Cull et al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390; Devlin (1990) Science 249:404-406; Cwirla et al. (1990) Proc. Natl. Acad. Sci. 87:6378-6382; Felici (1991) J. Mol. Biol. 222:301-310; Ladner supra.). 
     Design, Identification, and/or Characterization of GR Inhibitors 
     In some embodiments, test agents are selected randomly. In some embodiments, the present disclosure provides systems for designing, identifying and/or characterizing test agents. In some embodiments, test agents are designed, identified and/or characterized in vivo. In some embodiments, test agents are designed, identified and/or characterized in vitro. In some embodiments, test agents are designed, identified and/or characterized in silico. 
     In some embodiments designing, identifying and/or characterizing test agents in silico comprises the steps of: a) providing an image of target protein crystal (e.g., and SGK1, GR, or AR protein crystal) a GR crystal that includes at least one potential interaction site; b) docking in the image at least one moiety that is a potential GR inhibitor structural element; and c) assessing one or more features of a potential moiety-interaction site interaction. 
     In some embodiments, the one or more features include at least one feature selected from the group consisting of: spatial separation between the moiety and the potential interaction site; energy of the potential moiety-interaction site interaction, and/or combinations thereof. 
     In some embodiments, a method further comprises a step of providing an image of a potential GR inhibitor comprising the moiety docked with the image of the target GR crystal. In some embodiments, a method further comprises a step of comparing the image with that of an target GR crystal including a bound known modulator, substrate, or product. 
     Assessing Treatments 
     In some embodiments, the present invention provides technologies for identifying and/or characterizing potential treatments for CRPC and/or doubly resistant prostate cancer. For example, in accordance with the present invention, useful treatments modulate level and/or activity of GR. 
     In some embodiments, the invention presented herein comprises methods for identifying and/or characterizing agents for the treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer comprising contacting a system capable of expressing active e.g., in which active s present) with at least one test agent, determining a level or activity of the system when the agent is present as compared with a reference level or activity observed under otherwise comparable conditions when it is absent, and classifying the at least one test agent as a treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer if the level or activity of s significantly reduced when the test agent is present as compared with reference level or activity. 
     In some embodiments, the invention presented herein comprises methods for identifying and/or characterizing agents for the treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer comprising contacting a system capable of expressing active e.g., in which active GR is present) and also capable of expressing an appropriate reference entity (e.g., in which such a reference entity is present), and determining effect of the assessed agent on GR level or activity relative to that of the reference entity. In some embodiments, agents are identified and/or characterized as GR inhibitors as described herein 
     In which GR and AR are present and active with at least one test agent, determining a level or activity of GR in the system when the agent is present as compared with a GR reference level or activity observed under otherwise comparable conditions when it is absent, determining a level or activity of AR in the system when the agent is present as compared with an AR reference level or activity observed under otherwise comparable conditions when it is absent, classifying the at least one test agent as a treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer if the level or activity of GR is significantly reduced when the test agent is present as compared with the GR reference level or activity and the AR is not significantly increased when the test agent is present as compared with the AR reference level or activity. In some embodiments, the test agent is classified as a treatment of castration resistant prostate cancer and/or doubly resistant prostate cancer if the level or activity of AR is significantly reduced when the test agent is present as compared with the AR reference level or activity. 
     In some embodiments, the level or activity of GR comprises GR transcriptional activation activity. In some embodiments, the level or activity of GR comprises a GR mRNA level. In some embodiments, the level or activity of GR comprises a GR protein level. In some embodiments, the level or activity of AR comprises AR transcriptional activation activity. In some embodiments, the level or activity of AR comprises a AR mRNA level. In some embodiments, the level or activity of AR comprises a AR protein level. Methods for assaying mRNA and protein levels are described herein. 
     In some embodiments, a system comprises an expression system as described herein. 
     In some embodiments, a significant reduction in the level or activity of GR comprises a greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more reduction of GR level or activity. In some embodiments, a significant reduction in the level or activity of GR comprises a greater than 50% reduction of GR level or activity. 
     In some embodiments, a significant reduction in the level or activity of AR comprises a greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000% or more reduction of AR level or activity. In some embodiments, a significant reduction in the level or activity of AR comprises a greater than 50% reduction of AR level or activity. 
     In accordance with methods of the present invention, test agents are contacted with a system capable of expressing active and optionally AR) as described herein. Methods of contacting test agents to in vitro and in vivo systems are well known in the art. Methods of contacting test agents to in vitro systems include, but are not limited to, pipetting, mixing, or any other means of transferring a solid or liquid into cell culture or a cell free system. Methods of contacting test agents to in vivo systems include, but are not limited to direct administration to a target tissue, such as heart or muscle (e.g., intramuscular), tumor (intratumorally), nervous system (e.g., direct injection into the brain; intraventricularly; intrathecally). Alternatively or additionally, test agents can be administered by inhalation, parenterally, subcutaneously, intradermally, transdermally, or transmucosally (e.g, orally or nasally). More than one route can be used concurrently, if desired. 
     In some embodiments a reference GR and/or AR level or activity is determined. In some embodiments a reference GR and/or AR level or activity is determined concurrently with the determined GR and/or AR level or activity. In some embodiments, a reference GR and/or AR level or activity is determined historically relative to the determined GR and/or AR level or activity. In some embodiments, a reference GR and/or AR level or activity comprises a GR and/or AR level or activity that is observed in the system or a comparable system under comparable conditions lacking the test agent. In some embodiments, a reference GR and/or AR level or activity comprises the GR and/or AR level or activity that is observed in the system or a comparable system under otherwise identical conditions lacking the test agent. 
     In some embodiments, a reference GR and/or AR level or activity comprises the GR and/or AR level or activity that is observed in the system or a comparable system under comparable conditions that includes presence of a positive control agent. In some embodiments, a positive control agent comprises an agent characterized in that level or activity of GR and/or AR activation is higher in a GR and/or AR expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. 
     In some embodiments, a reference GR and/or AR level or activity comprises the GR and/or AR activation level or activity that is observed in the system or a comparable system under comparable conditions that include presence of a negative control agent. In some embodiments, a negative control agent comprises an SGK1 expression system when that system is contacted with the agent than under otherwise identical conditions when the system is not so contacted with the agent. Current invention provides methods of identifying and/or characterizing agents for treating or reducing incidence or risk for CRPC, comprising the determination of transcription level or activity of one or more targets of GR transcriptional activation contacted to a test agent and identifying the test agent as reducing incidence or risk for CRPC if the transcription level or activities are reduced relative to transcription level or activities in comparable conditions lacking the test agent. 
     Treatment 
     The present invention encompasses the recognition that SGK1, GR and/or AR inhibitors described herein, and combinations thereof, can be used as effective treatments for CRPC and doubly resistant prostate cancer. In some embodiments, the invention comprises methods for treating or reducing the risk of castration resistant prostate cancer comprising administering to a subject suffering from or susceptible to castration resistant prostate cancer a GR inhibitor. In some embodiments, the invention comprises methods for treating or reducing the risk of doubly resistant prostate cancer comprising administering to a subject suffering from or susceptible to doubly resistant prostate cancer a GR inhibitor. In some embodiments, the invention comprises methods for treating or reducing the risk of castration resistant prostate cancer comprising administering to a subject suffering from or susceptible to castration resistant prostate cancer an m the group consisting of AR inhibitors, GR inhibitors, and combinations thereof. In some embodiments, the invention comprises methods for treating or reducing the risk of castration resistant prostate cancer comprising administering to a subject suffering from or susceptible to castration resistant prostate cancer a combination of an AR inhibitor and a GR inhibitor, which combination is characterized in that its administration correlates with reduction in level or activity of SGK1 in a prostate cancer patient population. In some embodiments, the invention comprises methods for treating or reducing the risk of doubly resistant prostate cancer comprising administering to a subject suffering from or susceptible to doubly resistant prostate cancer a combination of an m the group consisting of AR inhibitors, GR inhibitors, and combinations thereof. In some embodiments, the invention comprises methods for treating or reducing the risk of doubly resistant prostate cancer comprising administering to a subject suffering from or susceptible to doubly resistant prostate cancer a combination of an AR inhibitor and a GR inhibitor, which combination is characterized in that its administration correlates with reduction in level or activity of SGK1 in a prostate cancer patient population. 
     In some embodiments, a subject suffering from or susceptible to castration resistant prostate cancer is a subject who has received castration therapy as described herein. 
     In some embodiments, a subject suffering from or susceptible to doubly resistant prostate cancer is a subject who has received both castration therapy and AR inhibitor therapy, as described herein. 
     In some embodiments, a subject suffering from or susceptible to CRPC is a subject with statistically significantly elevated levels of GR or of a GR-responsive entity such as SGK1. The present invention provides methods of identifying such subjects, and/or of monitoring the effect of therapy (e.g., of androgen inhibitor therapy), by detecting levels and/or activity of GR or a target thereof. In some embodiments, such monitoring may allow informed decisions to be made about continuing, terminating, and/or modifying therapy. 
     In some embodiments, methods of identifying subjects and/or of monitoring the effect of therapy in a subject include obtaining a sample from a subject and performing an analysis on the sample. In some embodiments, methods involve taking a plurality of samples over a designated period of time; in some such embodiments, samples are taken at regular intervals during or within the period of time. 
     Some particular embodiments of example analyses that may be performed on patient samples are set forth, for example, in Example 3. 
     In accordance with various embodiments of methods of the invention, an inhibitor described herein can be administered to a subject alone, or as a component of a composition or medicament (e.g., in the manufacture of a medicament for the prevention or treatment of CRPC or doubly resistant prostate cancer), as described herein. In some embodiments, a provided inhibitor can be formulated with a physiologically acceptable carrier or excipient to prepare a pharmaceutical composition. In some embodiments, a carrier utilized in such a pharmaceutical compositions, and/or the composition itself, can be sterile. In some embodiments, a pharmaceutical composition is formulated for a specific mode of administration. Methods of formulating compositions are known in the art (see, e.g., Remington&#39;s Pharmaceuticals Sciences, 17 th  Edition, Mack Publishing Co., (Alfonso R. Gennaro, editor) (1989)). 
     Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions (e.g, NaCl), saline, buffered saline, alcohols, glycerol, ethanol, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, sugars such as mannitol, sucrose, or others, dextrose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidone, etc., as well as combinations thereof. The pharmaceutical preparations can, if desired, be mixed with auxiliary agents (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like) which do not deleteriously react with the active compounds or interference with their activity. In a preferred embodiment, a water-soluble carrier suitable for intravenous administration is used. 
     The composition or medicament, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can also be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrollidone, sodium saccharine, cellulose, magnesium carbonate, etc. 
     The composition or medicament can be formulated in accordance with the routine procedures as a pharmaceutical composition adapted for administration to human beings. For example, in a preferred embodiment, a composition for intravenous administration typically is a solution in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the composition is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. 
     An inhibitor described herein can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. 
     An inhibitor described herein (or a composition or medicament containing an inhibitor described herein) is administered by any appropriate route. In some embodiments, an inhibitor is administered subcutaneously. As used herein, the term “subcutaneous tissue”, is defined as a layer of loose, irregular connective tissue immediately beneath the skin. For example, the subcutaneous administration may be performed by injecting a composition into areas including, but not limited to, thigh region, abdominal region, gluteal region, or scapular region. In some embodiments, an inhibitor is administered intravenously. In some embodiments, an inhibitor is administered orally. In other embodiments, an inhibitor is administered by direct administration to a target tissue, such as heart or muscle (e.g., intramuscular), tumor (intratumorallly), nervous system (e.g., direct injection into the brain; intraventricularly; intrathecally). Alternatively, an inhibitor (or a composition or medicament containing an inhibitor) can be administered by inhalation, parenterally, intradermally, transdermally, or transmucosally (e.g, orally or nasally). More than one route can be used concurrently, if desired. 
     In some embodiments, a composition is administered in a therapeutically effective amount and/or according to a dosing regimen that is correlated with a particular desired outcome (e.g., with treating or reducing risk for CRPC and/or doubly resistant prostate cancer). 
     Particular doses or amounts to be administered in accordance with the present invention may vary, for example, depending on the nature and/or extent of the desired outcome, on particulars of route and/or timing of administration, and/or on one or more characteristics (e.g., weight, age, personal history, genetic characteristic, lifestyle parameter, or combinations thereof). Such doses or amounts can be determined by those of ordinary skill. In some embodiments, an appropriate dose or amount is determined in accordance with standard clinical techniques. Alternatively or additionally, in some embodiments, an appropriate dose or amount is determined through use of one or more in vitro or in vivo assays to help identify desirable or optimal dosage ranges or amounts to be administered. 
     In various embodiments, an inhibitor is administered at a therapeutically effective amount. As used herein, the term “therapeutically effective amount” is largely determined based on the total amount of the inhibitor contained in the pharmaceutical compositions of the present invention. Generally, a therapeutically effective amount is sufficient to achieve a meaningful benefit to the subject (e.g., treating, modulating, curing, preventing and/or ameliorating the underlying disease or condition). In some particular embodiments, appropriate doses or amounts to be administered may be extrapolated from dose-response curves derived from in vitro or animal model test systems. 
     In some embodiments, a provided composition is provided as a pharmaceutical formulation. In some embodiments, a pharmaceutical formulation is or comprises a unit dose amount for administration in accordance with a dosing regimen correlated with achievement of the reduced incidence or risk of CPMC and/or doubly resistant prostate cancer. 
     In some embodiments, provided compositions, including those provided as pharmaceutical formulations, comprise a liquid carrier such as but not limited to water, saline, phosphate buffered saline, Ringer&#39;s solution, dextrose solution, serum-containing solutions, Hank&#39;s solution, other aqueous physiologically balanced solutions, oils, esters and glycols. 
     In some embodiments, a formulation comprising an inhibitor described herein administered as a single dose. In some embodiments, a formulation comprising an inhibitor described herein is administered at regular intervals. Administration at an “interval,” as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose). The interval can be determined by standard clinical techniques. In some embodiments, a formulation comprising an inhibitor described herein is administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, or every six hours. The administration interval for a single individual need not be a fixed interval, but can be varied over time, depending on the needs of the individual. 
     As used herein, the term “bimonthly” means administration once per two months (i.e., once every two months); the term “monthly” means administration once per month; the term “triweekly” means administration once per three weeks (i.e., once every three weeks); the term “biweekly” means administration once per two weeks (i.e., once every two weeks); the term “weekly” means administration once per week; and the term “daily” means administration once per day. 
     In some embodiments, a formulation comprising an inhibitor described herein is administered at regular intervals indefinitely. In some embodiments, a formulation comprising an inhibitor described herein is administered at regular intervals for a defined period. In some embodiments, a formulation comprising an inhibitor described herein is administered at regular intervals for 5 years, 4, years, 3, years, 2, years, 1 year, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, a month, 3 weeks, 2, weeks, a week, 6 days, 5 days, 4 days, 3 days, 2 days or a day. 
     Combination Therapy 
     In some embodiments, an inhibitor is administered in combination with one or more known therapeutic agents (e.g., anti-androgens) currently used for prostate cancer treatment and CPMC treatment as described herein (Table 1). In some embodiments, the known therapeutic agent(s) is/are administered according to its standard or approved dosing regimen and/or schedule. In some embodiments, the known therapeutic agent(s) is/are administered according to a regimen that is altered as compared with its standard or approved dosing regimen and/or schedule. In some embodiments, such an altered regimen differs from the standard or approved dosing regimen in that one or more unit doses is altered (e.g., reduced or increased) in amount, and/or in that dosing is altered in frequency (e.g., in that one or more intervals between unit doses is expanded, resulting in lower frequency, or is reduced, resulting in higher frequency). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Anti-androgen Drugs Currently Used Therapeutically 
               
            
           
           
               
               
               
            
               
                 Anti-androgen Drug 
                 Description 
                 Recommended Dosage 
               
               
                   
               
               
                 Leuprolide 
                 A luteinizing hormone-releasing 
                 Available in an injectable form and as an 
               
               
                   
                 hormone (LHRH) agonist, which 
                 implant. The implant form, used to treat 
               
               
                   
                 means that it resembles a chemical 
                 prostate cancer, contains 22.5 mg of 
               
               
                   
                 produced by the hypothalamus (a 
                 leuprolide and is inserted under the skin 
               
               
                   
                 gland located in the brain) that 
                 every three months. This type of slow- 
               
               
                   
                 lowers the level of testosterone in 
                 release medication is called depot form. A 
               
               
                   
                 the bloodstream. Also reduces 
                 longer-acting implant that lasts 12 months 
               
               
                   
                 levels of estrogen in girls and 
                 is also available. Injectable leuprolide is 
               
               
                   
                 women, and may be used to treat 
                 injected once a day in a 1-mg dose to treat 
               
               
                   
                 endometriosis or tumors in the 
                 prostate cancer. Dosage for endometriosis 
               
               
                   
                 uterus. It is presently under 
                 or uterine tumors is 3.75 mg injected into a 
               
               
                   
                 investigation as a possible 
                 muscle once a month for three to six 
               
               
                   
                 treatment for the paraphilias. 
                 months. 
               
               
                 Goserelin 
                 Also an LHRH agonist, and works 
                 Implanted under the skin of the upper 
               
               
                   
                 in the same way as leuprolide. 
                 abdomen. Dosage for treating cancer of 
               
               
                   
                   
                 the prostate is one 3.6-mg implant every 
               
               
                   
                   
                 28 days or one 10.8-mg implant every 12 
               
               
                   
                   
                 weeks. For treating endometriosis, dosage 
               
               
                   
                   
                 is one 3.6-mg implant every 28 days for 
               
               
                   
                   
                 six months. 
               
               
                 Triptorelin 
                 A LHRH agonist, and works in the 
                 Given as a long-lasting injection for 
               
               
                   
                 same way as leuprolide. Not 
                 treatment of prostate cancer or paraphilias. 
               
               
                   
                 usually given to women. 
                 Usual dose for either condition is 3.75 mg, 
               
               
                   
                   
                 injected into a muscle once a month. 
               
               
                 Abarelix 
                 Newer drug that works by 
                 Given in 100-mg doses by deep injection 
               
               
                   
                 blocking hormone receptors in the 
                 into the muscles of the buttocks. It is given 
               
               
                   
                 pituitary gland. Recommended for 
                 on days 1, 15, and 29 of treatment, then 
               
               
                   
                 the treatment of prostate cancer in 
                 every four weeks for a total treatment 
               
               
                   
                 men with advanced disease who 
                 duration of 12 weeks. 
               
               
                   
                 refuse surgery, cannot take other 
               
               
                   
                 hormonal treatments, or are poor 
               
               
                   
                 candidates for surgery. 
               
               
                 Ketoconazole 
                 An antifungal drug available in 
                 For treatment of hirsutism, 400 mg by 
               
               
                   
                 tablets to be taken by mouth. Its 
                 mouth once per day. 
               
               
                   
                 use in treating hirsutism is off- 
               
               
                   
                 label. 
               
               
                 Flutamide 
                 A nonsteroidal antiandrogen 
                 Available in capsule as well as tablet form. 
               
               
                   
                 medication that blocks the use of 
                 For treatment of prostate cancer, 250 mg 
               
               
                   
                 androgen by the body. 
                 by mouth three times a day. For 
               
               
                   
                   
                 virilization or hyperandrogenism in 
               
               
                   
                   
                 women, 250 mg by mouth three times a 
               
               
                   
                   
                 day. It should be used in women, however, 
               
               
                   
                   
                 only when other treatments have proved 
               
               
                   
                   
                 ineffective. 
               
               
                 Nilutamide 
                 Another nonsteroidal antiandrogen 
                 To treat prostate cancer, nilutamide is 
               
               
                   
                 drug that works by blocking the 
                 taken in a single 300-mg daily dose by 
               
               
                   
                 body&#39;s use of androgens. 
                 mouth for the first 30 days of therapy, then 
               
               
                   
                   
                 a single daily dose of 150 mg. 
               
               
                 Bicalutamide 
                 A nonsteroidal antiandrogen 
                 Taken by mouth in a single daily dose of 
               
               
                   
                 medication that works in the same 
                 50 mg to treat prostate cancer. 
               
               
                   
                 way as flutamide. 
               
               
                 Cyproterone acetate 
                 A steroidal antiandrogen drug that 
                 Taken by mouth three times a day in 100- 
               
               
                   
                 works by lowering testosterone 
                 mg doses to treat prostate cancer. Dose for 
               
               
                   
                 production as well as blocking the 
                 treating hyperandrogenism or virilization 
               
               
                   
                 body&#39;s use of androgens. 
                 in women is one 50-mg tablet by mouth 
               
               
                   
                   
                 each day for the first ten days of the 
               
               
                   
                   
                 menstrual cycle. Cyproterone acetate 
               
               
                   
                   
                 given to treat acne is usually given in the 
               
               
                   
                   
                 form of an oral contraceptive (Diane-35) 
               
               
                   
                   
                 that combines the drug (2 mg) with ethinyl 
               
               
                   
                   
                 estradiol (35 mg). Diane-35 is also taken 
               
               
                   
                   
                 as hormonal therapy by MTF transsexuals. 
               
               
                   
                   
                 The dose for treating paraphilias is 200- 
               
               
                   
                   
                 400 mg by injection in depot form every 
               
               
                   
                   
                 1-2 weeks, or 50-200 mg by mouth daily. 
               
               
                 Medroxyprogesterone 
                 A synthetic derivative of 
                 For the treatment of paraphilias, given as 
               
               
                   
                 progesterone that prevents 
                 an intramuscular 150-mg injection daily, 
               
               
                   
                 ovulation and keeps the lining of 
                 weekly, or monthly, depending on the 
               
               
                   
                 the uterus from breaking down, 
                 patient&#39;s serum testosterone levels, or as an 
               
               
                   
                 thus preventing uterine bleeding. 
                 oral dose of 100-400 mg daily. As 
               
               
                   
                   
                 hormonal therapy for MTF transsexuals, 
               
               
                   
                   
                 10-40 mg per day. For polycystic ovary 
               
               
                   
                   
                 syndrome, 10 mg daily for 10 days. 
               
               
                 Spironolactone 
                 A potassium sparing diuretic that 
                 For hyperandrogenism in women, 100-200 
               
               
                   
                 may be given to treat androgen 
                 mg per day by mouth; for polycystic ovary 
               
               
                   
                 excess in women. 
                 syndrome, 50-200 mg per day. For the 
               
               
                   
                   
                 treatment of acne, 200 mg per day. For 
               
               
                   
                   
                 hormonal therapy for MTF transsexuals, 
               
               
                   
                   
                 200-400 mg per day. A topical form of 
               
               
                   
                   
                 spironolactone is available for the 
               
               
                   
                   
                 treatment of androgenetic alopecia. 
               
               
                   
               
            
           
         
       
     
     EXAMPLES 
     Example 1: Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade 
     The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. The present disclosure demonstrates that resistance to such therapies can result from induction of glucocorticoid receptor (GR) expression. That is, the present disclosure demonstrates GR induction as a common feature of drug resistant tumors in a credentialed preclinical model, and furthermore confirms that this finding is also confirmed in patient samples. 
     As is identified herein, GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. The findings presented herein establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure, and furthermore define strategies for pharmacologically countering such escape. 
     Recently approved drugs that target androgen receptor (AR) signaling such as abiraterone and enzalutamide have rapidly become standard therapies for advanced stage prostate cancer (Scher et al., 2012b) (de Bono et al., 2011). Despite their success, sustained response with these agents is limited by acquired resistance which typically develops within 6-12 months. 
     Clinical success of kinase inhibitors in other tumors such as melanoma, lung cancer, leukemia and sarcoma is similarly transient (Sawyers et al., 2002) (Chapman et al., 2011) (Demetri et al., 2002) (Maemondo et al., 2010), resulting in numerous efforts to define mechanisms of acquired resistance. One strategy that has proven particularly useful in elucidating mechanisms of resistance to kinase inhibitors is prolonged treatment of drug-sensitive preclinical models to derive drug-resistant sublines, followed by genome-wide profiling studies to ascertain differences that may play a causal role in conferring drug resistance. A common mechanism that has emerged from these kinase inhibitor studies is reactivation of the signaling pathway targeted by the drug, whether directly (e.g., by mutation of the kinase target) or indirectly (e.g., by bypassing pathway inhibitor blockade through amplification of an alternative kinase) (Glickman and Sawyers, 2012). Both scenarios have been validated in clinical specimens and are guiding efforts to discover next generation inhibitors and to develop rational drug combinations. 
     Clinically relevant mechanisms of resistance to hormone therapy in prostate cancer have also been elucidated using preclinical models. Hormone therapy, through the use of drugs that lower serum testosterone or competitively block the binding of androgens to AR, has been the mainstay of treatment for metastatic prostate cancer for decades, but is not curative. The late stage of disease, which is refractory to hormone therapy, is termed castration resistant prostate cancer (CRPC). The molecular basis of progression to CRPC in mouse models was previously examined and it was discovered that increased AR expression was the primary mechanism (Chen et al., 2004). This observation was then used to screen for novel anti-androgens that restore AR inhibition in the setting of increased AR levels. These efforts yielded three second-generation anti-androgens: enzalutamide, ARN-509, and RD162 (Tran et al., 2009) (Clegg et al., 2012). Enzalutamide and ARN-509 were further developed for clinical use, culminating in FDA approval of enzalutamide in 2012 based on increased survival (Scher et al., 2012b). 
     Now with widespread use, resistance to enzalutamide is a major clinical problem. An AR point mutation has recently been identified as one resistance mechanism by derivation of drug-resistant sublines following prolonged exposure to enzalutamide or ARN-509 (Baibas et al., 2013) (Joseph et al., 2013) (Korpal et al., 2013). This AR mutation has also been recovered from patients with resistance to ARN-509 but only in a minority of cases (Joseph et al., 2013). The present invention establishes a novel and potentially more prevalent mechanism of resistance by which tumors bypass AR blockade through upregulation of the glucocorticoid receptor (GR). The present invention furthermore defines novel therapeutic modalities for the treatment of prostate cancer, including for the treatment of CRPC, through administration of inhibitory agents that target GR and/or that target one or more downstream markers responsive to GR. A particular such downstream marker of interest, as established herein, is SGK1. Such GR and/or SGK1 inhibitors may be administered alone, together, and/or in combination with one or more other cancer therapies (e.g., with an AR inhibitor such as an anti-androgen).) is described herein. 
     Methods 
     Cell lines: LNCaP/AR and VCaP cells were maintained as previously described (Tran et al., 2009). LREX′ cells were derived from a single enzalutamide resistant tumor that was harvested, disaggregated with collagenase treatment, and then maintained in RPMI supplemented with 20% FBS and 1 μM enzalutamide. Cells were initially grown on collagen-coated flasks until confluent and then were maintained on standard tissue culture dishes. CS1 were similarly derived from vehicle treated tumors and maintained in standard LNCaP/AR media. LNCaP/AR and LREX′ cells were cultured in phenol-red free RPMI with 10% charcoal-stripped FBS prior to drug treatments. 
     Xenografts: For all experiments, tumors measurements were obtained weekly using the average of three consecutively obtained volume measurements calculated from three-dimensional calipers measurements. LNCaP/AR xenografts were established in castrate mice as described previously (Tran et al., 2009). Once tumors were established, mice were treated with either enzalutamide, ARN-509, or RD162 (10 mg/kg), or vehicle alone (1% carboxymethyl cellulose, 0.1% Tween-80, 5% DMSO) 5 days a week by oral gavage. 4 day treated mice received ARN-509. Vehicle treated mice were harvested after either 4 or 28 days of treatment. For the validation cohort, 25 tumors were initiated on treatment with intention to continue until resistance, from which 19 resistant tissues were harvested (16 of which had attained a volume greater than at start of treatment.) Xenografts with LNCaP/AR sub-lines were established by injecting two million cells per flank into castrate mice. Mice injected with resistant sub-lines were initiated on treatment with enzalutamide (10 mg/kg) immediately after injection. For xenograft knock-down experiments, cells were infected with virus expressing a control (NT) or GR targeting hairpin, selected with puromycin treatment, and then implanted. 
     Global Transcriptome Analysis: RNA extracted from xenograft tumors was analyzed by either Affymetrix HuEx1 (pilot cohort) or Illumina HT-12 (validation cohort, LREX′) microarray. (A technical note: NR3C1 probe in Illumina HT-12 array appears to be non-functional and did not detect GR in any tissue, including LnCaP/AR cells engineered to express high levels.) For LREX′ in vitro analysis, cells were plated into steroid depleted media for 48 hours prior to drug treatment. Drug treatments were performed in triplicate with a final concentration of 1 nM DHT, 10 nM or 100 nM dexamethasone, and/or 10 μM enzalutamide for 8 hours. For VCaP in vitro analysis VCaP cells were maintained in standard media with complete fetal bovine serum and were treated in triplicate for 24 hours with vehicle, 0.1 nM DHT, 100 nM Dex, and/or 10 μM enzalutamide. All expression data was quantile normalized and analyzed with Partek software. 
     Chromatin Immuno-precipitation: LREX′ cells were maintained in steroid depleted media for 4 days. The day prior to drug treatment, cells were given fresh media. Material from two 15 cm plates of cells were divided for ChIP. For ChiP-seq, agonist stimulation was carried out for 30 minutes prior to harvest. Fixation and processing for was carried out as described by others (Goldberg et al., 2010). Immunoprecipitation was carried out with Anti-Androgen Receptor Antibody, PG-21 (Millipore) or Glucocorticoid Receptor Antibody #7437 (Cell Signaling). Immunoprecipitated DNA was quantified by picogreen and size was evaluated on a HighSense BioAnalyzer chip. Fragments between 100 and 600 bp were collected using an automated system (Pippin Prep, Sage Science) then end repaired, ligated and amplified for 15 cycles using reagents included in the Truseq DNA Sample Preparation kit from Illumina. Experimental conditions followed strictly the instructions of the manufacturer, with the exception of the adaptors being diluted 1/10 for the input DNA and 1/50 for all other samples. Barcoded libraries were run on a Hiseq 2000 in a 50 bp/50 bp paired end run, using the TruSeq SBS Kit v3 (Illumina). For ChiP-qPCR, ligand treatments were performed for 1 hour and fixation and processing was carried out using a chromatin immunoprecipitation assay kit (Millipore) in accordance with the manufacture&#39;s protocol. Immunoprecipitation was carried out with Anti-Androgen Receptor Antibody, PG-21 (Millipore), Glucocorticoid Receptor Antibody #3660 (Cell Signaling), or Normal Rabbit IgG (Millipore: 12-370). 
     ChIP-Seq data analysis: The sequencing reads (50 bp, paired-end) were aligned to the human genome (hg19, build 37) using the program Bowtie (Langmead et al., 2009). 8,201,777 and 18,876,986 reads from DHT-treated AR ChIP-seq and Dex-treated GR ChIP-seq LREX′ samples were aligned to a single genomic location with no more than two mismatches. These aligned reads were analyzed by the software MACS (Zhang et al., 2008) for peak identification with data from ChIP input DNAs as controls. The top 5,217 AR and 15,851 GR peaks were selected based on analysis of false discovery rate and peak intensities. Genes with peaks located from −50 kb of their transcription start sites to +5 kb of their transcription termination sites were defined as AR or GR targets, using the human RefSeq annotation as reference. The MEME software suite (Bailey et al., 2009) was applied to 100-bp sequences around the AR or GR peak summits for finding motifs, with the program MEME for motif discovery and MAST for motif scanning (p value &lt;0.001). 
     
       
         
           
               
               
            
               
                   
                 ChiP-PCR Primers: 
               
               
                   
                 SGK1 
               
               
                   
                 (SEQ ID NO: 30) 
               
               
                   
                 F: CTTCCCACCCACTTGTGCTT, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 31) 
               
               
                   
                 R: GAAAGGTGCCAGAGGAGACC; 
               
               
                   
                   
               
               
                   
                 FKBP5 
               
               
                   
                 (SEQ ID NO: 32) 
               
               
                   
                 F: CCCCCTATTTTAATCGGAGTAC, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 33) 
               
               
                   
                 R: TTTTGAAGAGCACAGAACACCCT; 
               
               
                   
                   
               
               
                   
                 KLK3 
               
               
                   
                 (SEQ ID NO: 34) 
               
               
                   
                 F: ATGTTCACATTAGTACACCTTGCC, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 35) 
               
               
                   
                 R: TCTCAGATCCAGGCTTGCTTACTGTC; 
               
               
                   
                   
               
               
                   
                 NDRG1 
               
               
                   
                 (SEQ ID NO: 36) 
               
               
                   
                 F: ATGGCCCCAGATATGTTCCA, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 37) 
               
               
                   
                 R: CCCAAGGTCTCAGAGCCAGT; 
               
               
                   
                   
               
               
                   
                 TIP ARP 
               
               
                   
                 (SEQ ID NO: 38) 
               
               
                   
                 F: CGTCTGGGGAGTAGGCAAAT, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 39) 
               
               
                   
                 R: CCCGAGGGAGGATGTGAAAC; 
               
               
                   
                   
               
               
                   
                 NR3C1 
               
               
                   
                 (SEQ ID NO: 40) 
               
               
                   
                 F: ACCAGACTGAATGTGCAAGC, 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 41) 
               
               
                   
                 R: AGGGTTTTTGATGGCACTGA 
               
            
           
         
       
     
     GR expression and GR/AR knockdown: shRNA knock-down experiments were carried out by infection of LREX′ or VCAP cells with MISSION® TRC2 pLK0.5-puro containing a non-targeting or GR specific hairpin (NT: GGGATAATGGTGATTGAGATGGCTCGAGCCAT CTCAATCACCATTATCCTTTTT (SEQ ID NO: 42), GR: CCGGCACAGGCTTCAGGTATCTTATCTCGAG ATAAGATACCTGAAGCCTGTGTTTTTG (SEQ ID NO: 43)). siRNA knock-down experiments were performed Dhamarcon SMARTpool: ON-TARGETplus AR siRNA, L-003400-00-0005 or ON-TARGETplus Non-targeting Pool, D-001810-10-20 according to manufactures protocol with a final concentration of 50 nM siRNA. For GR expression experiments, a stop codon was engineered into the NR3C1 alpha ORF (Origene RC204878) by PCR and then it was sub-cloned in pMItdT (a generous gift from Dr. Yu Chen, MSKCC.) pMItdT-EGFP was introduced into control cells. Infected cells were sorted by tdTomato expression using flow cytometry. 
     In vitro growth assays: VCaP; Cells were plated in triplicate and then assayed in triplicate at the time points indicated using CellTiter-Glo (Promega). Viability is plotted normalized to day 1. For knockdown studies, cells were infected and then plated 3 days later for the experiment without prior drug selection. LnCaP/AR and sub-lines; Equivalent numbers of cells were plated and then harvested and counted in triplicate at indicated time points using the Beckman Coulter Vi-Cell XR. Cells were passaged at each time point and identical numbers of cells re-plated. Fold increase in cell numbers were determined for each time interval. 
     Intracellular staining and flow cytometric analysis: Cells were re-suspended in Fixation/Permeabilization working solution (eBioscience; San Diego, Calif., USA) at a concentration of 1-2×10 6  cells/ml for 30 minutes at room temperature. The cells were subsequently stained with primary antibodies, Rabbit (DA1E) mAb IgG XP® Isotype Control, androgen receptor (D6F11) XP® Rabbit mAb, or glucocorticoid receptor (D6H2L) XP® Rabbit mAb (Cell Signaling Technology; Danvers, Mass., USA) for 20 minutes at room temperature. The cells were washed twice with Flow Cytometry Staining Buffer (eBioscience; San Diego, Calif., USA), and then stained with secondary antibody, Allophycocyanin-AffiniPure F(ab′) 2  Fragment Donkey Anti-Rabbit IgG (Jackson ImmunoResearch Laboratories, Inc.; Westgrove, Pa., USA) for 20 minutes at room temperature. Following two more washes, the cells were re-suspended in Flow Cytometry Staining Buffer and analyzed by flow cytometry on a LSRII (BD Biosciences; San Jose, Calif., USA) using FlowJo software (Tree Star, Ashland, Oreg., USA). For GR staining, cells were maintained in their standard media and treated with dexamethasone for 20 minutes prior to harvest to fully expose antigen. For AR staining, cells were cultured in charcoal stripped media without added ligands for 3 days prior to harvest. 
     RNA extraction and RT-qPCR analysis: RNA was extracted from cell lines using the RNeasy kit (Qiagen). Frozen tumors were lysed with lysing matrix A using the Fast-Prep24 tissue homogenizer system (MP BIOMEDICALS) in Trizol (Invitrogen) followed by clean up with RNeasy (Qiagen). cDNA was generated with the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems.) Data was quantified relative to either beta Actin or GAPDH expression and relative expression was generally plotted. Primers for ACTB (PPH00073E), NDRG7(PPH02202B), NR3C1 (PPH02652A), and SGK1 (PPH00387E), STK39 (PPH14239B), GRB10 (PPH05866B), TIP ARP (PPH07883A), PMEPA1 (PPH01013B) were purchased from SA Biosciences. Other qPCR primers are as follows: AR (F: CCATCTTGTCGTCAATGTTATGAAGC (SEQ ID NO: 44), R: AGCTTCTGGGTTGTCTCCTCAGTGG (SEQ ID NO: 45)), FKBP5 (F: CAGATCTCCATGTGCCAGAA (SEQ ID NO: 46), R: CTTGCCCATTGCTTTATTGG (SEQ ID NO: 47)), GAPDH (F: TGCACCACCAACTGCTTAGC (SEQ ID NO: 48), R: GGCATGGACTGTGGTCATGAG (SEQ ID NO: 49)) and KLK3 (F: GTCTGCGGCGGTGTTCTG (SEQ ID NO: 50), R: TGCCGACCCAGCAAGATC (SEQ ID NO: 51)). 
     Protein extraction and western blot analysis: Protein was extracted from cell lines using M-PER Reagent (Thermo Scientific). Protein was extracted from frozen tumors with lysing matrix A using the Fast-Prep 24 tissue homogenizer system (MP BioMedicals) using 1% SDS, 10 mM EDTA and 50 mM Tris, pH 8.0. Protein was quantified by BCA Protein Assay (Thermo Scientific). The following antibodies were used for western blots: anti-AR PG-21 at 1:5000 (Miilipore 06-680), anti-GR at 1:1000 (BD Transduction Laboratories 611227), β-actin at 1:20,000 (AC-15, Sigma), anti cPARP at 1:1000 (Cell Signaling #9541). 
     Cell line, xenograft and Tissue Microarray IHC: Cell line pellets or tumor pieces were fixed in 4% PFA prior to paraffin embedding and then were stained for GR at 1:200 with anti-glucocorticoid receptor (D6H2L) XP® Rabbit mAb (Cell Signaling Technology, #12041) using the Ventana BenchMark ULTRA. TMA was stained for GR at 1:200 with anti-glucocorticoid receptor (BD Transduction Laboratories #611227) using the Ventana BenchMark ULTRA. 
     Drugs: DHT and Dexamethasone were purchased from Sigma. ARN-509, RD162, and enzalutamide were all synthesized by the organic synthesis core at MSKCC. Compound 15 was a gift from Tom Scanlan (OHSU). All drugs were dissolved in DSMO in 1000× stocks. 
     Bone marrow evaluation: Patients were treated with enzalutamide 160 mg daily. Bone marrow biopsy and aspirate (˜5 mL) were performed before treatment and at week 8. The bone marrow specimens were obtained by transiliac biopsy, and samples were processed according to standard MD Anderson Cancer Center decalcification and fixation procedures. After pathologic evaluation, samples were stored in the MD Anderson Cancer Center Prostate Cancer Tissue Bank. Imaging studies were performed at the time of suspected prostate cancer progression or at the treating physician&#39;s discretion, but generally not prior to 12 weeks post-treatment initiation. Therapy was discontinued at the treating physician&#39;s discretion in patients exhibiting progression. Retrospective analysis for GR was performed by IHC on 3.5-mm formalin-fixed, paraffin-embedded bone marrow biopsy sections with anti-GR at a dilution of 1:200 (BD Transduction Laboratories #611227). A Dako autostainer and standard 3,3-diaminobenzidine were used. GR expression was assessed in a blinded fashion by two pathologists scoring at least 100 tumor cells per specimen. Plotted are either data from all specimens or only from patients with usable material at baseline and 8 weeks. 
     AR target gene list derivation: The 74 AR target gene list utilized for evaluation of AR pathway status in the LnCaP/AR model includes all genes that showed at least a 1.6-fold change (FDR&lt;0.05) when comparing control and 4 day treated xenografts and that were also found to have an AR binding peak by ChIP-seq analysis of LNCaP/AR in vitro (Cai et al, in preparation). The VCaP AR target gene list includes all genes that that showed reciprocal expression change with 24 hour DHT (0.1 nM) or enzalutamide (10 μM) of at least 1.4 fold (p&lt;0.05) (Illumina HT-12) and were also found to have an AR binding peak by ChIP-seq analysis of VCaP (Cai et al, in preparation). 
     AR/GR signature analysis and Gene Set Enrichment Analysis: AR and GR signature genes were defined as all genes showing &gt;1.6 fold (FDR&lt;05) expression change with either 1 nM DHT or 100 nM Dex treatment, respectively, of LREX′ cells for 8 hours in charcoal stripped media. For GSEA, signature genes induced by either DHT or Dex treatment were used. GR selective genes showed at least 1.1 fold higher expression in Dex treated samples compared to DHT treated samples (FDR&lt;0.05). AR selective genes showed at least a 1.1 fold higher expression in DHT treated samples compared to Dex treated samples (FDR&lt;05). 
     Statistics: Microarray data analysis and comparisons were performed with Partek Software. All RT-qPCR comparisons are by two-sided t-test. Xenograft volumes and GR IHC of clinical specimens are compared by one-sided Mann-Whitney test. In vitro growth comparisons are by two-sided t-test. GSEA statistical analysis was carried out with publicly available software from the Broad Institute (Cambridge, Mass.: http://www.broadinstitute.org/gsea/index.jsp). In all figures, *=&lt;0.05, **=&lt;0.01, ***=&lt;0.001, and ****=&lt;0.0001. 
     Results 
     GR is Expressed in Antiandrogen-Resistant Tumors 
     It was previously showed that LNCaP/AR xenograft tumors regress during the first 28 days of treatment with ARN-509 (Clegg et al., 2012), enzalutamide or RD162 (Tran et al., 2009). In a pilot study to explore mechanisms of acquired resistance to these drugs, mice were treated continually and harvested tumors after progression (mean 163 days, Table 2A). Tissue from fourteen resistant tumors obtained from long term antiandrogen treated mice (n=5 ARN-509, n=9 RD162) and from three control tumors from vehicle treated mice were analyzed by expression array. Aggregated data from resistant and control tumors in this pilot cohort were compared to identify expression changes commonly associated with resistance ( FIG. 1A ). Among the most up-regulated genes in the resistant tumors was the glucocorticoid receptor (GR, gene symbol NR3C1) which shares overlapping target specificity with AR (Mangelsdorf et al., 1995). Of note, several of the most differentially expressed genes were known androgen regulated genes (confirmed by transcriptome analysis of short term DHT treated LnCaP/AR cells, in vitro (Table 2B)), but they were altered in directions that did not reflect restored AR signaling. On the one hand, SGK1 (Serum Glucocorticoid Induced Kinase 1), a known AR and GR-induced target gene, was among the most up-regulated genes, but several other androgen-induced genes (PMEPA1, SNAI2, KCNN2, LONRF1, SPOCK1) were among the most repressed. Conversely, several androgen-repressed genes (UGT2B15, PMP22, CAMK2N1, UGT2B17) were among the most up-regulated ( FIG. 1A ). These findings indicated that resistance in this model system is unlikely to be mediated by simple restoration of AR activity and raised the possibility that GR may play a role. 
     To explore this question further, an independent set of drug-resistant tumors was generated (the validation cohort), focusing on the two second generation antiandrogens in clinical use, enzalutamide and ARN-509 ( FIG. 1B ). GR mRNA levels in 10 control, 8 short term treated (4 day) and 16 resistant tumors were substantially higher in resistant tissues compared to control (median 26.9-fold increase) or 4 day treated tumors ( FIG. 1C ). Of the tissues analyzed by RT-qPCR, most were also analyzed for GR expression by western blot, based on availability of protein lysates (control n=6, 4 day n=5, resistant n=13). No GR was detected in control samples, minimal expression was noted in 4 day treated samples, and substantial expression was found in most resistant tumors in a pattern that tended to correlate with GR mRNA levels ( FIG. 1D ). There was no correlation between GR expression and the specific antiandrogen treatment used. In contrast to GR, AR RNA or proteins levels were not consistently different across the treatment groups ( FIG. 1C, 1D ). 
     To explore AR and GR signaling in more detail, cells lines were established from control and drug-resistant tumors by adaptation to growth in vitro. LREX′ (LnCaP/AR Resistant to Enzalutamide Xenograft derived) was derived from an enzalutamide-resistant tumor with high GR expression, and CS1 was derived from a vehicle treated tumor. A flow cytometry-based assay to measure GR expression on a cell-by-cell basis was also developed. In both LNCaP/AR and CS1, most cells showed no evidence of GR expression, with the exception of a small subpopulation (black arrow, discussed later) ( FIG. 1E ). In contrast, essentially all LREX′ cells expressed GR. Intracellular AR staining confirmed that AR levels in LREX′ did not notably differ from control cells ( FIG. 2A ). 
     LREX′ Tumors are Dependent on GR for Enzalutamide-Resistant Growth 
     Having established the LREX′ model as representative of high GR expression, it was then confirmed that these cells maintain a resistant phenotype in vivo. LREX′ or control cells were injected into castrated mice that were then immediately initiated on antiandrogen treatment. LREX′ showed robust growth whereas LNCaP/AR or CS1 lines were unable to establish tumors in the presence of antiandrogen ( FIG. 3A,3B ). Strong expression of GR was confirmed in multiple LREX′ xenograft tumors by western blot and by IHC ( FIG. 2B, 2C ). Untreated LNCaP/AR tumors were negative for GR expression with the exception of rare GR-positive cells ( FIG. 3C ). Although many of these GR-positive cells had morphologic features of stromal or endothelial cells (blue arrows), some appeared epithelial (black arrow), consistent the with flow cytometry analysis ( FIG. 1E , black arrows). 
     To determine whether GR expression is required to maintain the drug-resistant phenotype, LREX′ cells were infected with a shRNA targeting GR (shGR) and stable knockdown of GR protein was confirmed ( FIG. 3F ). Tumor growth of shGR infected LREX′ cells was significantly delayed relative to shNT (non targeted)-infected cells in castrated mice treated with enzalutamide ( FIG. 3D ). In contrast, shGR had no impact on the growth of GR-negative CS1 xenografts, diminishing the possibility of an off-target effect ( FIG. 3E ). Of note, shGR LREX′ xenografts harvested on day 49 showed decreased GR protein knockdown compared to the pre-implantation levels, indicative of selective pressure against GR silencing in the setting of enzalutamide treatment ( FIG. 3F ). These findings provide direct evidence that GR drives enzalutamide resistance in vivo. 
     GR Expression is Associated with Clinical Resistance to Enzalutamide 
     To determine whether GR expression is a feature of clinical antiandrogen resistance, GR expression was evaluated in bone metastases from patients receiving enzalutamide. Bone marrow samples were obtained prior to enzalutamide treatment (baseline) and again after 8 weeks of treatment, as previously reported in a cohort of abiraterone-treated patients (Efstathiou et al., 2012). Using a GR IHC assay optimized for use in bone marrow samples, the percentage of GR-positive tumor cells was quantified and the data was dichotomized based on clinical response. Patients who continued to benefit from therapy for greater than 6 months were defined as good responders, while those in whom therapy was discontinued earlier than 6 months due to a lack of clinical benefit were classified as poor responders ( FIG. 5A ). Consistent with the designation of good versus poor clinical response based on treatment status at 6 months, 11 of 13 good responders but only 1 of 14 poor responders had a maximal PSA decline greater than 50% ( FIG. 5C ). Akin to the findings in the preclinical model, GR positivity at baseline was low: 3% of tumor cells in good responders and 8% in poor responders. Of note, 3 of 22 tumors had evidence of high GR expression at baseline (&gt;20% of tumor cells) and all three had a poor clinical response ( FIG. 5C ,D). At 8 weeks, the mean percentage of GR positive cells was higher than baseline levels in both response groups but was more significantly elevated in poor responders (29% vs 8%, p=0.009). In addition, the percentage of GR-positive cells at 8 weeks was significantly higher in poor compared to good responders (29% versus 10%, p=0.02) ( FIG. 5C ,D), and similar results were obtained when the analysis was limited to patients from whom matched baseline and 8 week samples were available for analysis ( FIG. 5E ). Furthermore, when GR IHC data was dichotomized based on PSA decline instead of clinical response, GR induction was also associated with a limited PSA decline ( FIG. 4 ). These findings establish a correlation between GR expression and clinical response to enzalutamide and raise the possibility that AR inhibition may induce GR expression in some patients. The fact that PSA levels also correlate with GR expression raises the question of whether transcriptional regulation of a canonical AR target gene may be regulated by GR. 
     GR Expressing Drug-Resistant Tumors Show Uneven Restoration of AR Target Genes 
     Having implicated GR as a potential mediator of antiandrogen resistance, it was next determined whether restored AR pathway activity also plays a role by comparing the mRNA transcript levels of 74 direct AR target genes in control, 4 day, and resistant tumors from the validation cohort ( FIGS. 5A-E ) as well as eight LREX′ tumors ( FIG. 7A ). 
     Consistent with the data generated in the pilot cohort ( FIG. 1A ), some AR target genes in resistant tissues showed elevated levels relative to control (SGK1, STK39) while other genes (NDRG1, TIPARP, PMEPA1) showed no evidence of restored expression. 
     To examine restoration of AR signaling across the entire set of 74 target genes, a fractional restoration value was calculated using log 2 transformed expression values and the equation (Resistant−4 day)/(Control−4 day). With this approach, a gene whose expression in resistant tissue equals the expression in control tumors calculates as 1, while a gene whose expression in resistance equals its expression after 4 days of antiandrogen treatment equals 0. (Values greater than one indicate hyper-restoration in resistance relative to control and values below zero suggest further inhibition as compared to acute treatment.) These data confirmed that the pattern of restoration varied gene by gene, but this pattern was consistent in LREX′ xenografts and in the validation cohort tumors (Pearson r 0.64, p=7.54×10 −10 ,  FIG. 7B ). This finding is most consistent with a model in which AR remains inhibited in drug-resistant tumors but expression of certain AR target genes is restored by an alternative transcription factor, possibly GR. The fact that AR restoration values were somewhat higher in the LREX′ analysis correlates with higher GR expression in these tumors ( FIG. 7C ). 
     GR Drives Expression of AR Target Genes in Resistant Tissues 
     To determine if GR can drive expression of this subset of AR target genes, in vitro, DHT-induced (AR) and dexamethasone (Dex)-induced (GR) expression of 7 AR targets that represent the spectrum of restoration noted in the in vivo analysis were compared, as well as PSA ( FIG. 7D ). All 8 genes were regulated by DHT, and this regulation was blocked by enzalutamide. Thus, AR signaling remains intact and can be inhibited by antiandrogens in these drug-resistant cells, making an AR-dependent mechanism of drug resistance less likely. 
     In contrast to DHT, the effect of Dex on these same target genes was variable but closely matched the pattern observed in drug resistant xenografts. For example, Dex strongly induced SGK1 and STK39 but did not induce HP ARP, NDRG1, and PMEPA1. Of note, KLK3 (PSA) was comparably induced by either DHT or Dex, providing evidence that persistent PSA expression in patients responding poorly to enzalutamide could be driven by GR. As expected, enzalutamide did not notably affect Dex activity. To confirm that this pattern of GR-dependent gene expression is not unique to LREX′ cells, GR expressing retrovirus was introduced into parental LNCaP/AR cells and a similar pattern of DHT- versus Dex-induced gene expression was observed ( FIG. 8A, 8B ). To be sure that the effects of Dex in these models are mediated through GR, cells were co-treated with a previously described competitive GR antagonist that lacks AR binding called compound 15 (Wang et al., 2006). Compound 15 significantly decreased expression of Dex-induced genes, confirming that Dex activity in the LREX′ model is GR-dependent ( FIG. 8C ). Lastly, siRNA experiments targeting AR confirmed that AR is not necessary for Dex-mediated gene activation ( FIG. 8D ). Collectively these experiments demonstrate that GR is able to drive expression of certain AR target genes independent of AR. 
     AR and GR have Overlapping Transcriptomes and Cistromes 
     To explore AR and GR transcriptomes in an unbiased fashion, expression profiling after short-term treatment of LREX′ cells with DHT or Dex was performed in the presence or absence of enzalutamide. AR and GR signatures were respectively defined as all genes with absolute expression change greater than 1.6 fold (FDR&lt;05) after 1 nM DHT or 100 nM Dex treatment (Table 4). Of the 105 AR signature genes and 121 GR signature genes, 52 were common to both lists ( FIG. 9A ). An even larger proportion of AR or GR signature genes (&gt;80%) showed evidence of regulation by the reciprocal receptor using different thresholds for expression differences (Table 4). Heatmap analysis of these genes confirmed significant overlap in DHT- versus Dex-induced gene expression and showed that Dex-induced gene expression is not impacted by enzalutamide treatment ( FIG. 9B ). These findings support the hypothesis that GR activity can bypass enzalutamide-mediated AR inhibition by regulating a distinct but significantly overlapping transcriptome. 
     Whether transcriptomes of enzalutamide-resistant tumors are more likely to be explained by AR- or GR-driven gene expression using gene set enrichment analysis (GSEA) was next addressed. To define gene sets that distinguish AR and GR activity, expression of AR and GR signature genes was first evaluated by GSEA in the DHT- and Dex-treated samples from which they were derived. As expected, GR signature genes were enriched in the Dex-treated samples and AR signature genes were enriched with DHT treatment ( FIG. 9C ). Because several of the genes did not distinguish AR and GR status due to their overlapping transcriptional activities, the lists were refined into AR selective genes (defined as the AR induced signature genes that were also more highly expressed in DHT treated samples relative to Dex treated samples, n=39) and GR selective genes (defined as the converse, n=67) (Table 4). GSEA analysis of these selective gene lists revealed that GR selective genes were strongly enriched in the enzalutamide-resistant LREX′ tumors whereas AR selective genes were strongly enriched in the control tumors ( FIG. 9D ). These data provide compelling, unbiased evidence that drug resistance is associated with a transition from AR- to GR-driven transcriptional activity. 
     One prediction of this model is that GR should occupy a substantial portion of AR binding sites in drug resistant cells. To address this question, ChIP-seq experiments were conducted to define AR and GR DNA binding sites in LREX′ cells after DHT and Dex treatment respectively. Of note, 52% of the AR binding sites identified after DHT treatment were bound by GR after Dex treatment ( FIG. 9E ). The remaining 48% of AR peaks were examined more closely to be sure that these peaks were not scored as GR negative simply because they fell just below the threshold set by our peak calling parameters. When the average AR and GR signal was plotted as a measure of the relative strength of AR and GR peaks, little evidence was found of GR binding at the AR unique sites ( FIG. 10A ), confirming that these peaks were indeed unique to AR. Next motif analysis was conducted to explore potential differences between AR/GR overlap versus AR unique sites. The core ARE/GRE consensus sequence was present in both groups (66% and 68% of peaks) but AR/GR overlap peaks were relatively enriched for the FoxA1 motif (64% versus 45% of peaks, p=2.2×10-16) ( FIG. 9E ). Similar analysis of the GR cistrome defined GR unique and AR/GR overlap peaks and revealed that a higher proportion of GR binding sites were unique to GR. Interestingly, GR unique peaks were highly enriched for the FoxA motif ( FIG. 9F ), while the classic ARE/GRE was not reported by the motif discovery algorithm (MEME) and was found only 25% of the time. 
     Although these cistrome studies provide evidence of substantial overlap between AR and GR binding sites in enzaluamide-resistant cells, several lines of evidence indicate that the transcriptional differences in DHT- versus Dex-induced gene expression cannot be explained solely by DNA binding. For example, ChIP RT-qPCR experiments showed significant AR and GR DNA binding at genes induced by both receptors (SGK1, FKBP5, PSA) but also at genes such as NDRG1 that are transcriptionally activated by DHT but not Dex ( FIG. 10B ). Integrative ChIP-seq and transcriptome analysis provided further evidence that DNA binding is not sufficient to determine transcriptional competence. Of the 56 AR signature genes found to have an AR binding peak, 49 showed at least some transcriptional regulation by GR (1.2 fold expression change, p&lt;05). 38 of these 49 GR regulated genes (78%) had an overlapping AR/GR binding peak, confirming substantial overlap at co-regulated genes. But GR peaks were also found in 3 of the 7 AR targets genes (43%) with no apparent GR transcriptional regulation ( FIG. 10C ). Others have reported evidence of allosteric regulation of hormone receptor complexes by specific DNA sequences independent of binding affinity (Meijsing et al., 2009), a phenomenon that may also be relevant here. 
     Activation of GR by Dexamethasone is Sufficient to Confer Enzalutamide Resistance 
     Whereas LNCaP/AR cells acquire GR expression after prolonged exposure to enzalutamide, some prostate cancer cell lines derived from CRPC patients (DU145, PC3, VCaP) express endogenous GR ( FIG. 11A ). DU145 and PC3 cells are AR-negative and hence resistant to enzalutamide but VCaP cells are enzalutamide-sensitive in vitro (Tran et al., 2009). IHC analysis showed diffuse, primarily cytoplasmic GR expression under standard culture conditions that lack glucocorticoid supplementation ( FIG. 12A ). To test if GR activation by addition of glucocorticoids impacts antiandrogen sensitivity, VCaP cells were treated with enzalutamide in the presence or absence of Dex. Enzalutamide inhibited growth as expected, but co-treatment with Dex reversed this growth inhibition ( FIG. 11B ). Additional studies with the GR antagonist, compound 15, or with GR. shRNA restored enzalutamide sensitivity, provided pharmacologic and genetic evidence that GR confers resistance ( FIG. 11C, 11D, 11E ). Of note, GR knockdown (which inhibits GR more completely than compound 15, which has mixed agonist/antagonist properties (Wang et al., 2006)) augmented the activity of enzalutamide even in the absence of Dex ( FIG. 11D ,F), suggesting that even the weak basal GR activity seen under our standard cultures conditions can confer relative resistance to enzalutamide. This result also suggests that a pure GR antagonist could enhance the activity of enzalutamide in prostate cancers co-expressing GR and AR. 
     To determine if Dex activates a subset of AR target genes in VCaP (as observed in the LREX′ model), a list of AR target genes was derived in VCaP cells exposed to DHT and it was asked whether Dex could modulate these same AR target genes in the presence of enzalutamide. Dex restored expression of some targets (KLK2, FKBP5, HOMER2, SLC45A3) but not others (DHCR24, SLC2A3, TRPM8, TMEM79), analogous to the uneven restoration observed in the LNCaP/AR model ( FIG. 11G ). Dex also induced expression of the clinical biomarker PSA in these cells, further supporting the hypothesis that GR can drive PSA progression in enzalutamide-resistant patients ( FIGS. 12B , C). To confirm that Dex activated genes via the glucocorticoid receptor, the effect of compound 15 was evaluated on Dex induced transcriptional activity. As expected, compound 15 reduced Dex induction of the GR targets KLK2 and FKBP5 ( FIG. 11H ). Similarly, GR knock-down prevented Dex-mediated induction of target genes ( FIG. 12C ). As in the LREX′ system (Table 4), the vast majority of genes robustly regulated by GR activation in VCaP cells were also regulated by AR activation with DHT (Table 5). These findings extend the hypothesis that GR promotes enzalutamide resistance largely by replacing AR activity at a subset of genes to a second model system. 
     A Subset of Prostate Cancers are Primed for GR Induction in the Setting of AR Inhibition 
     In considering potential mechanisms for increased GR expression in drug-resistant tumors, several observations were noted that suggested two distinct models. First, flow cytometry analysis of LNCaP/AR and CS1 cells revealed GR expression in a rare subset of cells ( FIG. 1E ), raising the possibility that these cells clonally expand under the selective pressure of antiandrogen therapy. Consistent with this model, rare GR-positive cells were observed in a tissue microarray analysis of 59 untreated primary prostate cancers (Table 6). However, a modest (˜2 fold) but significant increase in GR mRNA levels in LNCaP/AR xenografts was observed after only 4 days of antiandrogen treatment, reminiscent of an older report of increased GR expression in normal ventral rat prostate after castration (Davies and Rushmere, 1990). These findings suggest a second model of adaptive resistance whereby AR inhibition causes an increase in GR levels due to loss of AR-mediated negative feedback. 
     To investigate the relationship between AR activity and GR expression, whether the high level of GR expression in LREX′ tumors is maintained after discontinuation of enzalutamide was examined. Remarkably, GR mRNA levels dropped by ˜5 fold 8 days after treatment discontinuation ( FIG. 13A ). Because enzalutamide has a prolonged half-life in mice (Tran et al., 2009), it is difficult to make definitive conclusions about negative feedback loops using in vivo models. Therefore, similar enzalutamide withdrawal experiments were conducted in LREX′ cells cultured in vitro. GR mRNA levels dropped as early as 1 day after discontinuation and continued to decline throughout the 23 days of the experiment ( FIG. 13B ). Additional experiments with LREX′ cells using earlier timepoints in charcoal stripped media showed reduced GR mRNA levels after only 8 hours DHT exposure and this reduction was reversed by co-treatment with enzalutamide ( FIG. 13C ). This reduction correlated precisely with the recruitment of an AR binding peak in an intronic enhancer of GR identified by ChIP, suggesting AR directly represses GR expression in these cells ( FIG. 13D ). 
     To determine if the loss of GR expression upon enzalutamide withdrawal occurs across the entire cell population or is restricted to a subset of cells, flow cytometry experiments were conducted, where a shift in median signal intensity can be used to identify expression changes in the bulk cell population. (Expression changes limited to a minority sub-population would not affect the median and would instead be identified as a tail population by histogram plot.) An exponential decay in median GR protein signal was observed (half-life 7.6 days) ( FIG. 13E , top row,  13 F), confirming that the loss in GR expression occurs across the entire LREX′ cell population. Extension of this experiment to later time points (17 weeks) revealed a plateau in loss of GR expression by 7 weeks ( FIG. 14A ). 
     Next the reciprocal experiment of re-exposure of LREX′ cells to enzalutamide following GR downregulation after prolonged enzalutamide withdrawal (LREX′ off ) was conducted. GR expression was regained with induction kinetics essentially reciprocating the rate of decay previously seen with removal of drug (doubling time 6.8 days), establishing that the resistant line remained poised for GR induction in the setting of AR inhibition ( FIG. 13E ,F). Consistent with the time scale, continued drug exposure for 7 weeks was associated with a clear shift in GR expression in essentially all cells ( FIG. 14A ). 
     It was next determined if AR inhibition is sufficient to induce GR expression in LNCaP/AR or CS1 cells that had not previously been exposed to enzalutamide. In contrast to LREX′, there was no change in median expression intensity in CS1 or LnCaP/AR over the 4 week experiment, indicating that most cells do not turn on GR expression simply as a consequence of AR inhibition ( FIGS. 13E, 13F, 14C ). However, the area under the GR staining population did increase. Given the weak antiproliferative effect of enzalutamide in vitro ( FIG. 14B ), the results presented herein suggest that this increase in GR expression is most likely explained by loss of AR-mediated negative feedback rather than by clonal expansion. Together, these findings support a model in which a subset of prostate cancer cells are “primed” for GR induction in the context of AR inhibition through an adaptive resistance mechanism (via AR-mediated negative feedback). The results presented herein suggest that these cells then clonally expand under the selective pressure of AR blockade, eventually emerging as drug-resistant tumors whose expression profiles may resemble those of AR-driven tumors but are driven by GR ( FIG. 13G ). 
     
       
         
           
               
             
               
                 TABLE 2A 
               
             
            
               
                   
               
               
                 Pilot Cohort 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Mean Tumor 
                   
                 Mean Tumor 
                   
               
               
                 Anti- 
                 Volume 
                 % 
                 Volume 
                 Day of 
               
               
                 Androgen 
                 (mm 3 ): 
                 Regression: 
                 (mm 3 ) at 
                 Harvest: 
               
               
                 Group 
                 Day 0 
                 D 28 Mean 
                 harvest 
                 Mean 
               
               
                   
               
               
                 All (n = 15) 
                 364 
                 76% 
                 467 
                 D 163 
               
               
                 RD162 (n = 9) 
                 379 
                 80% 
                 554 
                 D 173 
               
               
                 ARN-509 (n = 6) 
                 341 
                 71% 
                 337 
                 D 145 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 2B 
               
               
                   
                   
               
               
                   
                 Illumina HT-12 data 
                 LNCAP/AR 
                   
               
               
                   
                 Probeset ID 
                 Fold Change with DHT 
                 p-value 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 SGK1 
                 7.05 
                 1.98E−12 
               
               
                   
                 KCNN2 
                 2.85 
                 1.17E−09 
               
               
                   
                 PMEPA1 
                 2.76 
                 8.22E−10 
               
               
                   
                 NCAPD3 
                 2.39 
                 1.31E−06 
               
               
                   
                 SNAI2 
                 2.03 
                 4.77E−09 
               
               
                   
                 LONRF1 
                 1.68 
                 4.36E−06 
               
               
                   
                 SPOCK1 
                 1.66 
                 1.70E−05 
               
               
                   
                 UGT2B17 
                 −1.26 
                 0.000392588 
               
               
                   
                 UGT2B15 
                 −1.36 
                 0.00216714  
               
               
                   
                 CAMK2N1 
                 −3.33 
                 1.34E−07 
               
               
                   
                 PMP22 
                 −4.49 
                 1.31E−12 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2C 
               
             
            
               
                   
               
               
                 Validation Cohort 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Drug 
                 GR mRNA 
                 Western 
                 Other Resistance 
               
               
                   
                 Treatment 
                 Expression 
                 Blot 
                 Mechanism 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 ARN 
                 172.1 
                 Y 
                   
               
               
                   
                 Enz 
                 127.7 
                 Y 
               
               
                   
                 ARN 
                 103.8 
                 Y 
               
               
                   
                 Enz 
                 53.0 
                 N 
               
               
                   
                 ARN 
                 47.4 
                 Y 
               
               
                   
                 ARN 
                 41.6 
                 Y 
               
               
                   
                 ARN 
                 30.2 
                 Y 
               
               
                   
                 Enz 
                 29.8 
                 N 
               
               
                   
                 Enz 
                 24.2 
                 Y 
               
               
                   
                 Enz 
                 24.0 
                 Y 
               
               
                   
                 ARN 
                 14.5 
                 Y 
               
               
                   
                 Enz 
                 14.3 
                 N 
               
               
                   
                 ARN 
                 11.4 
                 Y 
                 AR mutation 
               
               
                   
                 ARN 
                 1.4 
                 Y 
               
               
                   
                 ARN 
                 0.8 
                 Y 
               
               
                   
                 Enz 
                 0.5 
                 Y 
                 CDH2 expressing 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Fractional Restoration of AR targets in resistance 
               
            
           
           
               
               
               
            
               
                   
                 Fractional Restoration 
                 Fractional Restoration 
               
               
                 Probeset 
                 Resistant (Validation Cohort) 
                 LREX′ 
               
               
                   
               
            
           
           
               
               
               
            
               
                 ADAMTS1 
                 0.104737035 
                 0.224681263 
               
               
                 ARHGAP28 
                 0.298572591 
                 1.112766385 
               
               
                 ATAD2 
                 0.980888318 
                 1.302557125 
               
               
                 ATP1B1 
                 0.054334091 
                 1.552059641 
               
               
                 AURKA 
                 1.055812896 
                 1.012376027 
               
               
                 C11ORF82 
                 1.022088793 
                 0.879681046 
               
               
                 C12ORF26 
                 0.559908334 
                 0.856561712 
               
               
                 C14ORF4 
                 0.638697558 
                 1.686188564 
               
               
                 C7ORF68 
                 0.57401979 
                 1.169336795 
               
               
                 CAP2 
                 0.953992059 
                 0.69853094 
               
               
                 CCNA2 
                 0.732665467 
                 1.071889661 
               
               
                 CKB 
                 1.066887783 
                 1.021144279 
               
               
                 COBL 
                 0.575676657 
                 1.028916763 
               
               
                 COL4A5 
                 1.383819191 
                 1.816840842 
               
               
                 COLEC12 
                 0.884755155 
                 1.134950911 
               
               
                 CYBASC3 
                 0.618319396 
                 0.622717671 
               
               
                 DDC 
                 0.252818617 
                 1.346416329 
               
               
                 ENPP5 
                 0.872211171 
                 1.566327079 
               
               
                 ERBB2 
                 0.584956319 
                 0.450288253 
               
               
                 ERRFI1 
                 0.344869039 
                 0.791369105 
               
               
                 FADS1 
                 0.783280213 
                 1.534588169 
               
               
                 FAM111A 
                 1.06151086 
                 1.91087708 
               
               
                 FKBP5 
                 0.507369877 
                 0.746124849 
               
               
                 GINS2 
                 0.818809571 
                 0.993454642 
               
               
                 GLRX2 
                 0.163895682 
                 0.394469677 
               
               
                 GMNN 
                 1.437188789 
                 2.125173731 
               
               
                 GRB10 
                 0.661692232 
                 1.464197128 
               
               
                 HK2 
                 0.857807757 
                 0.944175379 
               
               
                 HMMR 
                 0.586811723 
                 0.611488201 
               
               
                 HOMER2 
                 0.718856843 
                 0.835066652 
               
               
                 IRX3 
                 1.504573197 
                 2.101495745 
               
               
                 IRX5 
                 1.58503456 
                 2.04652588 
               
               
                 KCNN2 
                 0.50426061 
                 −0.058662743 
               
               
                 LAMA5 
                 0.594448349 
                 1.614096978 
               
               
                 LOC338758 
                 1.10031621 
                 1.892542273 
               
               
                 LOC643911 
                 1.430495646 
                 1.277746127 
               
               
                 LPAR3 
                 0.223276924 
                 0.760020748 
               
               
                 MAPK6 
                 0.6794877 
                 0.712027157 
               
               
                 MELK 
                 0.822946788 
                 0.951119531 
               
               
                 MLF1IP 
                 0.801888795 
                 0.320087012 
               
               
                 NCAPG 
                 0.830147149 
                 0.930073778 
               
               
                 NDC80 
                 0.858582224 
                 0.931146158 
               
               
                 NDRG1 
                 0.110736515 
                 −0.89658973 
               
               
                 NLGN1 
                 0.452084841 
                 1.549812463 
               
               
                 NRP1 
                 0.735034964 
                 1.018946919 
               
               
                 ODC1 
                 0.685851438 
                 0.758202603 
               
               
                 PLEKHB1 
                 1.006632446 
                 1.321859712 
               
               
                 PLXDC2 
                 1.457006773 
                 1.696602557 
               
               
                 PMEPA1 
                 −0.518193024 
                 −1.216512966 
               
               
                 PPFIA2 
                 0.399925636 
                 1.270985117 
               
               
                 PRKD1 
                 0.730293325 
                 1.553606953 
               
               
                 PTGER4 
                 0.500131315 
                 1.14695717 
               
               
                 PTGFR 
                 −0.163702714 
                 1.289011102 
               
               
                 RND3 
                 1.462746581 
                 1.845253498 
               
               
                 SEMA6A 
                 0.324521397 
                 1.214013023 
               
               
                 SESN1 
                 0.500071071 
                 1.204301228 
               
               
                 SGK 
                 1.594552221 
                 3.860391513 
               
               
                 SGK1 
                 0.908306288 
                 2.583445858 
               
               
                 SLC45A3 
                 0.666206634 
                 0.572479739 
               
               
                 SLC7A5 
                 1.788159088 
                 1.505143938 
               
               
                 SMA4 
                 1.007154273 
                 1.905171027 
               
               
                 SORL1 
                 0.393127568 
                 0.792003324 
               
               
                 STK39 
                 0.847407901 
                 1.627660166 
               
               
                 TIPARP 
                 0.091937709 
                 −0.095853867 
               
               
                 TK1 
                 1.103253735 
                 1.239068469 
               
               
                 TLL1 
                 0.042830568 
                 0.578273664 
               
               
                 TMEM38B 
                 0.52248819 
                 0.967647176 
               
               
                 TPX2 
                 0.969128419 
                 0.760244607 
               
               
                 TRIM45 
                 0.797043275 
                 1.170614157 
               
               
                 TSC22D3 
                 0.502868149 
                 0.808846273 
               
               
                 TSKU 
                 0.60338297 
                 1.278936716 
               
               
                 TTK 
                 0.650518354 
                 0.807578623 
               
               
                 TXNIP 
                 0.761305485 
                 1.155255054 
               
               
                 ZWILCH 
                 0.621821416 
                 0.45158825 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 AR and GR signature genes corresponding to FIG. 9. Top: GR signature 
               
               
                 genes showing at least modest regulation by AR, or conversely, 
               
               
                 AR signature genes showing at least modest regulation by GR 
               
               
                 are annotated. Most (&gt;80%) AR and GR signature genes show 
               
               
                 some evidence of regulation by the reciprocal receptor. Bottom: 
               
               
                 GR and AR selective genes used for GSEA analysis 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 GR signature 
                 Significant 
                 AR signature 
                 Significant 
               
               
                 probesets 
                 regulation by 
                 probesets 
                 regulation by 
               
               
                 (Dex 1.6 fold 
                 AR (DHT 1.20 
                 (DHT 1.6 fold 
                 GR (Dex 1.20 
               
               
                 FDR &lt; .05) 
                 fold p &lt; .05)? 
                 FDR &lt; .05) 
                 fold p &lt; .05)? 
               
               
                   
               
               
                 ABCC4 
                 Y 
                 ABCC4 
                 Y 
               
               
                 ABHD2 
                 Y 
                 ALDH1A3 
                 Y 
               
               
                 ACTA2 
                 N 
                 BAMBI 
                 Y 
               
               
                 ALDH1A3 
                 Y 
                 BDNF 
                 Y 
               
               
                 ATAD2 
                 N 
                 C17ORF48 
                 Y 
               
               
                 AZGP1 
                 N 
                 C19ORF48 
                 Y 
               
               
                 BAMBI 
                 Y 
                 C1ORF116 
                 Y 
               
               
                 BCL6 
                 N 
                 CBLN2 
                 Y 
               
               
                 BRDT 
                 Y 
                 CEBPD 
                 Y 
               
               
                 C11ORF92 
                 Y 
                 CHST2 
                 Y 
               
               
                 C17ORF48 
                 Y 
                 CRISPLD2 
                 Y 
               
               
                 C19ORF48 
                 Y 
                 CROT 
                 N 
               
               
                 C1ORF116 
                 Y 
                 CYP7A1 
                 Y 
               
               
                 C1ORF149 
                 Y 
                 DKFZP761P0423 
                 N 
               
               
                 C6ORF85 
                 Y 
                 DNM1L 
                 Y 
               
               
                 C7ORF63 
                 Y 
                 EDG7 
                 Y 
               
               
                 C9ORF152 
                 N 
                 ELL2 
                 Y 
               
               
                 CEBPD 
                 Y 
                 ENDOD1 
                 N 
               
               
                 CGNL1 
                 N 
                 ERN1 
                 Y 
               
               
                 CHKA 
                 Y 
                 ERRFI1 
                 Y 
               
               
                 CRY2 
                 Y 
                 F2RL1 
                 Y 
               
               
                 DBC1 
                 Y 
                 FAM105A 
                 Y 
               
               
                 DDIT4 
                 Y 
                 FAM110B 
                 Y 
               
               
                 EDG7 
                 Y 
                 FAM113B 
                 Y 
               
               
                 EEF2K 
                 Y 
                 FAM49A 
                 Y 
               
               
                 ELL2 
                 Y 
                 FKBP5 
                 Y 
               
               
                 EMP1 
                 N 
                 FRK 
                 Y 
               
               
                 ERRFI1 
                 Y 
                 FZD5 
                 Y 
               
               
                 F2RL1 
                 Y 
                 GADD45G 
                 Y 
               
               
                 FAM105A 
                 Y 
                 GCNT1 
                 Y 
               
               
                 FAM49A 
                 Y 
                 GCNT3 
                 Y 
               
               
                 FKBP5 
                 Y 
                 GRHL2 
                 Y 
               
               
                 FLJ22795 
                 Y 
                 HERC5 
                 Y 
               
               
                 FOXO3 
                 Y 
                 HEY1 
                 Y 
               
               
                 GADD45B 
                 Y 
                 HMOX2 
                 Y 
               
               
                 GHR 
                 Y 
                 HS.25318 
                 Y 
               
               
                 HERC5 
                 Y 
                 KIAA0194 
                 N 
               
               
                 HMOX2 
                 Y 
                 KLF15 
                 Y 
               
               
                 HOMER2 
                 Y 
                 KLF5 
                 Y 
               
               
                 HS.99472 
                 Y 
                 KLK2 
                 Y 
               
               
                 HSD11B2 
                 Y 
                 KLK4 
                 Y 
               
               
                 IL6R 
                 Y 
                 LIPG 
                 Y 
               
               
                 KBTBD11 
                 Y 
                 LPAR3 
                 Y 
               
               
                 KIAA0040 
                 N 
                 LRIG1 
                 Y 
               
               
                 KIAA1370 
                 Y 
                 MBOAT2 
                 Y 
               
               
                 KLF15 
                 Y 
                 MGC87042 
                 Y 
               
               
                 KLF5 
                 Y 
                 MLPH 
                 Y 
               
               
                 KLF9 
                 N 
                 MTMR9 
                 Y 
               
               
                 KLK3 
                 Y 
                 MUC13 
                 Y 
               
               
                 KLK4 
                 Y 
                 NAPEPLD 
                 Y 
               
               
                 KRT80 
                 Y 
                 NAT8B 
                 N 
               
               
                 LIN7B 
                 N 
                 NDRG1 
                 Y 
               
               
                 LINCR 
                 Y 
                 NEDD4L 
                 Y 
               
               
                 LOC100008588 
                 Y 
                 NFKBIA 
                 Y 
               
               
                 LOC100130886 
                 Y 
                 NKX3-1 
                 Y 
               
               
                 LOC100131392 
                 Y 
                 NPPC 
                 N 
               
               
                 LOC100134006 
                 N 
                 ORM1 
                 N 
               
               
                 LOC340970 
                 Y 
                 ORM2 
                 N 
               
               
                 LOC346702 
                 Y 
                 PAK1IP1 
                 Y 
               
               
                 LOC399939 
                 Y 
                 PDE9A 
                 Y 
               
               
                 LOC440040 
                 N 
                 PIK3AP1 
                 Y 
               
               
                 LOC648509 
                 Y 
                 PMEPA1 
                 Y 
               
               
                 LOC728431 
                 N 
                 PMP22 
                 N 
               
               
                 LPAR3 
                 Y 
                 PPFIBP2 
                 Y 
               
               
                 MAP3K8 
                 Y 
                 PRAGMIN 
                 Y 
               
               
                 MBOAT2 
                 Y 
                 PRR15L 
                 Y 
               
               
                 MEAF6 
                 Y 
                 PSCD1 
                 N 
               
               
                 MGC87042 
                 Y 
                 PSD 
                 Y 
               
               
                 MT1X 
                 N 
                 RAB20 
                 Y 
               
               
                 MTMR9 
                 Y 
                 RASD1 
                 Y 
               
               
                 NDRG1 
                 Y 
                 RDH10 
                 Y 
               
               
                 NEDD4L 
                 Y 
                 RHOU 
                 Y 
               
               
                 NFKBIA 
                 Y 
                 RND3 
                 Y 
               
               
                 NKX3-1 
                 Y 
                 RNF160 
                 Y 
               
               
                 NPC1 
                 Y 
                 SGK 
                 Y 
               
               
                 NRP1 
                 Y 
                 SGK1 
                 Y 
               
               
                 PDE9A 
                 Y 
                 SHRM 
                 Y 
               
               
                 PER1 
                 Y 
                 SIPA1L2 
                 Y 
               
               
                 PGC 
                 N 
                 SLC16A6 
                 Y 
               
               
                 PGLYRP2 
                 N 
                 SLC26A3 
                 Y 
               
               
                 PHLDA1 
                 Y 
                 SLC2A12 
                 Y 
               
               
                 PLGLB1 
                 Y 
                 SLC2A3 
                 N 
               
               
                 PNLIP 
                 Y 
                 SLC36A1 
                 N 
               
               
                 PPAP2A 
                 N 
                 SLC45A3 
                 Y 
               
               
                 PRKCD 
                 Y 
                 SNAI2 
                 Y 
               
               
                 PRR15L 
                 Y 
                 SNORD54 
                 Y 
               
               
                 PSD 
                 Y 
                 SPSB1 
                 Y 
               
               
                 RASD1 
                 Y 
                 ST6GALNAC1 
                 N 
               
               
                 RDH10 
                 Y 
                 STEAP2 
                 Y 
               
               
                 RGS2 
                 N 
                 SYTL2 
                 Y 
               
               
                 RHOB 
                 Y 
                 TIPARP 
                 N 
               
               
                 RHOU 
                 Y 
                 TMPRSS2 
                 Y 
               
               
                 RND3 
                 Y 
                 TSC22D1 
                 Y 
               
               
                 RNF160 
                 Y 
                 TSKU 
                 Y 
               
               
                 S100P 
                 Y 
                 TUBA3C 
                 Y 
               
               
                 SCNN1G 
                 N 
                 TUBA3D 
                 Y 
               
               
                 SGK 
                 Y 
                 TUBA3E 
                 Y 
               
               
                 SGK1 
                 Y 
                 UAP1 
                 N 
               
               
                 SIPA1L2 
                 Y 
                 VASN 
                 Y 
               
               
                 SLC25A18 
                 Y 
                 WNT7B 
                 N 
               
               
                 SLC26A3 
                 Y 
                 ZBTB16 
                 Y 
               
               
                 SLC2A12 
                 Y 
                 ZMIZ1 
                 Y 
               
               
                 SLC31A2 
                 Y 
                 ZNF385B 
                 N 
               
               
                 SLC45A3 
                 Y 
                 ZNF533 
                 N 
               
               
                 SNAI2 
                 Y 
                 ZNF703 
                 N 
               
               
                 SPRYD5 
                 N 
               
               
                 SPSB1 
                 Y 
               
               
                 STEAP2 
                 Y 
               
               
                 STK39 
                 Y 
               
               
                 SYTL2 
                 Y 
               
               
                 TBC1D8 
                 Y 
               
               
                 TMPRSS2 
                 Y 
               
               
                 TRIM48 
                 Y 
               
               
                 TSKU 
                 Y 
               
               
                 TUBA3C 
                 Y 
               
               
                 TUBA3D 
                 Y 
               
               
                 TUBA3E 
                 Y 
               
               
                 ZBTB16 
                 Y 
               
               
                 ZC3H12A 
                 Y 
               
               
                 ZMIZ1 
                 Y 
               
               
                 ZNF812 
                 N 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 GR selective gene set 
                 AR selective gene set 
               
               
                   
                   
               
               
                   
                 ABHD2 
                 ABCC4 
               
               
                   
                 ACTA2 
                 C1ORF116 
               
               
                   
                 ATAD2 
                 CROT 
               
               
                   
                 AZGP1 
                 DKFZP761P0423 
               
               
                   
                 BCL6 
                 ENDOD1 
               
               
                   
                 C1ORF149 
                 ERN1 
               
               
                   
                 C6ORF85 
                 FAM110B 
               
               
                   
                 C7ORF63 
                 FRK 
               
               
                   
                 C9ORF152 
                 FZD5 
               
               
                   
                 CEBPD 
                 GADD45G 
               
               
                   
                 CGNL1 
                 GCNT1 
               
               
                   
                 CHKA 
                 GRHL2 
               
               
                   
                 CRY2 
                 HEY1 
               
               
                   
                 DBC1 
                 KIAA0194 
               
               
                   
                 DDIT4 
                 LRIG1 
               
               
                   
                 EEF2K 
                 MTMR9 
               
               
                   
                 EMP1 
                 NDRG1 
               
               
                   
                 ERRFI1 
                 NKX3-1 
               
               
                   
                 FKBP5 
                 NPPC 
               
               
                   
                 FLI22795 
                 ORM1 
               
               
                   
                 FOXO3 
                 ORM2 
               
               
                   
                 GADD45B 
                 PAK1IP1 
               
               
                   
                 GHR 
                 PIK3AP1 
               
               
                   
                 HERC5 
                 PMEPA1 
               
               
                   
                 HOMER2 
                 PRAGMIN 
               
               
                   
                 HSD11B2 
                 PSCD1 
               
               
                   
                 KBTBD11 
                 RASD1 
               
               
                   
                 KIAA0040 
                 RHOU 
               
               
                   
                 KLF15 
                 SHRM 
               
               
                   
                 KLF9 
                 SLC2A3 
               
               
                   
                 KRT80 
                 SLC36A1 
               
               
                   
                 LIN7B 
                 SLC45A3 
               
               
                   
                 LOC100130886 
                 TIPARP 
               
               
                   
                 LOC100131392 
                 TMPRSS2 
               
               
                   
                 LOC100134006 
                 TSC22D1 
               
               
                   
                 LOC340970 
                 UAP1 
               
               
                   
                 LOC399939 
                 WNT7B 
               
               
                   
                 LOC440040 
                 ZNF385B 
               
               
                   
                 LOC728431 
                 ZNF533 
               
               
                   
                 MEAF6 
               
               
                   
                 MT1X 
               
               
                   
                 NPC1 
               
               
                   
                 NRP1 
               
               
                   
                 PGC 
               
               
                   
                 PGLYRP2 
               
               
                   
                 PHLDA1 
               
               
                   
                 PNLIP 
               
               
                   
                 PPAP2A 
               
               
                   
                 PRKCD 
               
               
                   
                 PRR15L 
               
               
                   
                 RGS2 
               
               
                   
                 RHOB 
               
               
                   
                 S100P 
               
               
                   
                 SCNN1G 
               
               
                   
                 SGK 
               
               
                   
                 SGK1 
               
               
                   
                 SLC25A18 
               
               
                   
                 SPRYD5 
               
               
                   
                 SPSB1 
               
               
                   
                 STK39 
               
               
                   
                 TRIM48 
               
               
                   
                 TUBA3C 
               
               
                   
                 TUBA3D 
               
               
                   
                 TUBA3E 
               
               
                   
                 ZBTB16 
               
               
                   
                 ZMIZ1 
               
               
                   
                 ZNF812 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Regulation of GR regulated Genes in VCAP by AR 
               
            
           
           
               
               
               
            
               
                   
                 VCAP: Dex Regulated 
                   
               
               
                   
                 Genes (1.5 fold, FDR &lt; .05) 
                 Significant change 
               
               
                   
                 Gene 
                 with DHT? 
               
               
                   
                   
               
               
                   
                 ACSL3 
                 Yes (FDR &lt; .05) 
               
               
                   
                 C21ORF34 
                 Yes (FDR &lt; .05) 
               
               
                   
                 CAMK2N1 
                 Yes (FDR &lt; .05) 
               
               
                   
                 CXCR7 
                 Yes (FDR &lt; .05) 
               
               
                   
                 EAF2 
                 Yes (FDR &lt; .05) 
               
               
                   
                 ELL2 
                 Yes (FDR &lt; .05) 
               
               
                   
                 ERRFI1 
                 Yes (FDR &lt; .05) 
               
               
                   
                 FKBP5 
                 Yes (FDR &lt; .05) 
               
               
                   
                 HOMER2 
                 Yes (FDR &lt; .05) 
               
               
                   
                 HS.570267 
                 Yes (FDR &lt; .05) 
               
               
                   
                 MYBPC1 
                 Yes (FDR &lt; .05) 
               
               
                   
                 OPRK1 
                 Yes (FDR &lt; .05) 
               
               
                   
                 REG4 
                 Yes (FDR &lt; .05) 
               
               
                   
                 SEC11C 
                 Yes (FDR &lt; .05) 
               
               
                   
                 STK39 
                 Yes (FDR &lt; .05) 
               
               
                   
                 ZCCHC6 
                 Yes (FDR &lt; .05) 
               
               
                   
                 ARHGAP28 
                 Yes (p &lt; .05) 
               
               
                   
                 C11ORF92 
                 Yes (p &lt; .05) 
               
               
                   
                 CAPN5 
                 Yes (p &lt; .05) 
               
               
                   
                 CEBPD 
                 Yes (p &lt; .05) 
               
               
                   
                 CRELD2 
                 Yes (p &lt; .05) 
               
               
                   
                 HSPA5 
                 Yes (p &lt; .05) 
               
               
                   
                 KLF9 
                 Yes (p &lt; .05) 
               
               
                   
                 PDIA4 
                 Yes (p &lt; .05) 
               
               
                   
                 SGK1 
                 Yes (p &lt; .05) 
               
               
                   
                 TRA1P2 
                 Yes (p &lt; .05) 
               
               
                   
                 ZBTB16 
                 Yes (p &lt; .05) 
               
               
                   
                 MAOA 
                 No 
               
               
                   
                 SCNN1A 
                 No 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 GR staining (IHC) of Tissue Microarray 
               
            
           
           
               
               
               
               
            
               
                   
                 Primary (untreated) PCa 
                 n = 59 
                 Median 
               
               
                   
                 Distribution 
                 # of tumors 
                 Intensity (1-3) 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                 Absent 
                 34 
                 0 
               
               
                   
                 Focal 
                 6 
                 1 
               
               
                   
                 Low 
                 7 
                 1 
               
               
                   
                 Intermediate 
                 11 
                 1 
               
               
                   
                 Diffuse 
                 1 
                 2 
               
               
                   
                   
               
               
                   
                 Distribution (% of cells staining): Absent = 0%, Focal &lt;20%, Low 20-50%, Intermediate 50-90%, Diffuse &gt;90% 
               
            
           
         
       
     
     DISCUSSION 
     Following the recent approvals of the next generation AR pathway inhibitors abiraterone and enzalutamide, the treatment of metastatic prostate cancer has evolved to a two-stage process. Initially patients receive conventional androgen deprivation therapy, typically with a gonadotropin-releasing hormone agonist that lowers testosterone (castration), often in conjunction with an anti-androgen such as bicalutamide. Preclinical and clinical studies have conclusively demonstrated that acquired resistance to conventional androgen deprivation therapy is caused by restoration of AR pathway activation, primarily due to increased AR expression. These discoveries provided the rationale for the development of next generation AR therapies. 
     The results presented herein demonstrate that acquired resistance to at least one of these new next generation therapies, enzalutamide, can occur via a different mechanism—increased expression of GR. The evidence for GR-driven resistance emerged from two independent preclinical models (LNCaP/AR and VCaP) and was supported by correlative data showing increased GR expression in patients with enzalutamide resistance. Consistent with mechanistic studies showing that GR can function independently of AR, increased GR expression was also associated with ARN-509 resistance, potentially forecasting a general mechanism of resistance to antiandrogens. Whether increased GR expression plays a role in abiraterone resistance remains to be determined. Unlike enzalutamide and ARN-509, abiraterone impairs AR signaling by lowering residual systemic and intratumoral androgen levels and preclinical evidence suggests that abiraterone resistance may be associated with increased AR expression (Mostaghel et al., 2011). The results presented herein suggest that tumors can efficiently overcome the ligand deficiency conferred by traditional androgen-deprivation therapy or abiraterone by simply elevating AR levels, whereas the increased selection pressure conferred by second-generation antiandrogens requires an alternative strategy such as GR bypass or AR mutation (Baibas et al., 2013; Joseph et al., 2013; Korpal et al., 2013). 
     Comparative AR and GR transcriptome studies supported a model whereby GR bypasses enzalutamide-mediated AR blockade without the need for any restored AR function. This model is further supported by ChIP-seq analyses showing that GR can bind to just over half of all AR binding sites in enzalutamide resistant cells. Importantly, GR occupied a large number of sites that are not bound by AR, raising the possibility of a distinct GR transcriptional program that could contribute to resistance. However, transcriptome analysis found that a large majority of genes robustly regulated by GR were also regulated by AR. For this reason, the results presented herein suggest that the antiandrogen resistance conferred by GR is most likely mediated by one or more of the unevenly restored AR target genes rather than a distinct set of “GR only” target genes. It will be of interest to explore whether just one or a small number of downstream targets are responsible for resistance and also why GR fails to activate transcription at the vast majority of the “GR unique” binding sites. It is postulated that variables such as chromatin context, co-factors and other signaling events may be important. 
     The GR bypass model of AR pathway blockade presented herein is reminiscent of recent reports that kinase inhibitor blockade in various cancers can be overcome by up-regulation of other kinases and/or their ligands (Engelman et al., 2007; Johannessen et al., 2010; Straussman et al., 2012; Wilson et al., 2012). The results presented herein comprise the first example of nuclear receptor bypass as a mechanism of acquired resistance to nuclear receptor blockade. In the case of kinase inhibitors, bypass is just one of many potential resistance mechanisms that also includes direct mutation of the kinase target and lineage switching to histologically distinct phenotypes that no longer require the drug target for survival (Katayama et al., 2012). The same may be true here based on the fact that a subset of drug-resistant LNCaP/AR tumors had minimal GR expression, raising the possibility of other resistance drivers. For example, one of these low GR tumors contained the F876L AR mutation that converts both ARN-509 and enzalutamide to agonists and is associated with clinical resistance (Baibas et al., 2013; Joseph et al., 2013; Korpal et al., 2013). A second low GR tumor expressed high levels of N-Cadherin (Table 2C), which can confer AR independence by morphological conversion to a tumor with mesenchymal features (Tanaka et al., 2010). 
     Expression of GR in antiandrogen-resistant prostate tumors appears to occur by a mechanism that includes features of adaptive resistance (via AR-mediated negative feedback of GR expression) as well as clonal selection. The results presented herein showed that AR inhibition induced strong GR expression in drug-resistant prostate cancer cells as well as in a subset of drug-naïve cells that are somehow “primed” to respond. The molecular basis for this “primed” state remains to be defined but, based on the reversibility of GR expression in the presence or absence of AR inhibition, is likely to involve an epigenetic mechanism. Knowledge of baseline tumor GR expression in patients, as well as the “primed” state of these tumor cells, could have clinical relevance as a treatment response biomarker. Baseline GR expression may predict a poor clinical outcome and, based on the increase in GR expression in some patients after 8 weeks of treatment, that the “priming” phenomenon observed in the models presented herein may also be relevant in patients. 
     Whatever the precise mechanism regulating GR expression, one immediate implication is that corticosteroid therapy could be detrimental to prostate cancer patients in certain clinical contexts. Corticosteroids are currently administered routinely with both docetaxel and abiraterone to prevent side effects from each of these therapies. The data presented herein suggest that corticosteroids might promote tumor progression in men whose tumors express GR. Indeed, reanalysis of the phase 3 clinical trial AFFIRM that demonstrated a survival benefit with enzalutamide treatment found that men receiving corticosteroids had a significantly worse survival that those who did not (Scher et al., 2012b) (Scher et al., 2012a). It is worth noting that corticosteroids can also confer clinical benefit in CRPC, an effect attributed to feedback suppression of pituitary ACTH production and resultant decrease in adrenal androgen production (Attard et al., 2009). This duality of potential glucocorticoid effects should prompt a reexamination of the appropriate clinical context for corticosteroid therapy. 
     The data presented herein also suggest that combined inhibition of both GR and AR could prolong the duration of response with next generation AR antagonists. Clinical studies of the GR antagonist mefipristone in patients with excess glucocorticoid production (Cushing syndrome) demonstrate that GR can be inhibited in humans with an acceptable risk-benefit profile (Fleseriu et al., 2012). Unfortunately both mefipristone and a related GR antagonist ORG34517 activate AR target gene expression, likely by direct AR agonism since mefipristone binds and activates AR (Klokk et al., 2007). The ability of compound 15 to overcome GR driven resistance should stimulate further efforts to optimize GR-specific antagonists that lack “off target” AR effects for use in preventing or overcoming enzalutamide resistance. 
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         Scher, H. I., Fizazi, K., Saad, F., Taplin, M. E., Sternberg, C. N., Miller, K., de Wit, R., Mulders, P., Chi, K. N., Shore, N. D., et al, (2012b), Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England journal of medicine 367, 1187-1197. 
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         Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008). Model-based analysis of ChIP-Seq (MACS). Genome Biol 9, R137. 
       
    
     Example 2: Traditional Androgen Treatments for Prostate Cancer 
       
                     TABLE 6               Prescribing information for the antiandrogen flutamide                                        Indication &amp; Dosage   Oral           Palliative treatment of prostatic carcinoma           Adult: 250 mg tid preferably at least 3 days           before gonadorelin analogue treatment.       Administration   May be taken with or without food.       Contraindications   Hypersensitivity, severe hepatic impairment,           pregnancy and lactation.       Hypersensitivity, severe   Perform liver function tests before starting       hepatic impairment,   treatment and at regular intervals. Treatment       pregnancy and lactation.   is not recommended in patients whose ALT           values exceed twice the upper limit of normal.           Regular assessment of prostate specific antigen           level may help to monitor disease progression.           Advise patient against discontinuing drug on           their own. Exercise caution in patients with           cardiac disease.       Adverse Drug Reactions   Hot flushes, loss of libido, impotence,           gynaecomastia, nausea, vomiting, diarrhoea,           increased appetite, sleep disturbances, skin           reactions, anaemias, headache, dizziness,           malaise, anxiety, hypertension, gastric and           chest pain, oedema, blurred vision, hepatitis,           jaundice, rash, thirst, pruritus, SLE-like           syndrome, drowsiness, confusion, depression,           nervousness.       Drug Interactions   Increased prothrombin time in patients on           long-term warfarin treatment.           Potentially Fatal: Increased prothrombin time           in patients on long-term warfarin treatment.       Pregnancy Category   Category D: There is positive evidence of       (US FDA)   human foetal risk, but the benefits from use in           pregnant women may be acceptable despite the           risk (e.g., if the drug is needed in a life-           threatening situation or for a serious disease for           which safer drugs cannot be used or are           ineffective).       Storage   Oral: Store at 25° C.       Mechanism of Action   Flutamide is a nonsteroidal ‘pure’ antiandrogen           which acts directly on the target tissues either           by blocking androgen uptake or by inhibiting           cytoplasmic and nuclear binding of androgen.           Distribution: Protein-binding: 90%           Metabolism: Rapid and extensive; converted to           hydroxyflutamide.           Excretion: Urine, faeces (small amounts); 2 hrs           (elimination half-life, metabolite).       MIMS Class   Hormonal Chemotherapy       ATC Classification   L02BB01 - flutamide; Belongs to the class of           anti-androgens.                    
From http://www.mims.com/USA/drug/info/flutamide/?type=full&amp;mtype=generic
 
     Example 3: Characterization of ABR173 and ABR167 
     Due to the need for a potent GR antagonist with either no AR activity or with potent dual AR/GR antagonism, “rational” design of derivatives with the desired pharmacology was performed based on molecular modeling of AR/GR ligands. 
     As described above, DU145 cells are AR-negative and hence resistant to enzalutamide. Under these conditions, GR-dependent proliferation was examined. The two compounds of interest, ABR173 and ABR167, performed comparably to ORG 34517 (ORG) in assays with different concentrations of dexamethasone (Dex) ( FIG. 15 ). 
     The novel compounds were also tested in a luciferase reporter assay in CSS media, utilizing retroviral Probasin-AR luciferase reporter. As shown in vehicle treated cells, neither ABR173 nor ABR167 had much agonist ability in this assay, though ABR167 did have a bit more than ABR173. Both compounds were effective at reversing the effect of Dex, a GR agonist, but not so successful at reversing the effect of DHR, an AR agonist ( FIG. 16 ). 
     In order to characterize the novel compounds in respect to their activation of endogenous genes in cells, LREX′ cells in CSS were used. The compounds were tested in cells treated with vehicle or DHT+Dex (AR agonist and GR agonist). Additionally, some cells were tested with the novel compounds given individually, and others with a novel compound plus enzalutamide. The results demonstrate that ABR173 and ABR167 do not show agonist ability and both demonstrate dual GR/AR antagonist activity ( FIG. 17 ). 
     As described previously, LNCaP cells were used for an AR responsive GFP reporter assay in Fetal Bovine Serum (FBS). The novels compounds ABR173 and ABR167 were similarly effective to Enz/ARN-509 in this assay ( FIG. 18 ). In cells engineered to overexpress AR, the novel compounds ABR173 and ABR167 were not as effectively antagonistic as Enz/ARN-509 ( FIG. 19 ). However, in LNCAP cells that overexpress the AR mutant AR F876L, the novel compounds ABR173 and ABR167 were more effective antagonists than Enz/ARN-509 ( FIG. 20 ). 
     Both novel compounds were tested in LREX′ cell line cultures in FBS with 1 μM Enz to examine their effects on endogenous target genes. All 3 genes examined were induced by Dex and both ABR173 and ABR167 demonstrated mild agonist activity ( FIG. 21 ). 
     An assay in VCaP cells (high levels of GR, low levels of AR) was performed to determine if the novel compounds could overcome the effect of Dex (GR agonist) without impairing the effect of Enz (AR antagonist). Both ABR173 and ABR167 blocked the Dex-induced resistance to Enz without compromising Enz function ( FIG. 22 ). Additionally, the effect of ABR167+Enz is quite promising. The experiment was repeated with ABR173 because there might have been some non-specific effects due to a precipitate in an older batch of the compound. In this experiment, higher doses ABR173 appeared to slightly impair Enz efficacy ( FIG. 23 ). 
     Finally, Western blots were performed to assess the effect of the novel compounds on AR and GR protein levels. Both ABR173 and ABR167 appeared to cause some GR protein degradation ( FIG. 24 ). 
     Example 4: Three Dimensional Modeling Analyses 
     This Example describes the use of three-dimensional X-ray modeling data in the rational design of GR and AR inhibitors described herein (e.g., compounds of formula I). As described in Appendices C and D, modeling analyses were performed to understand which parts of known GR/AR inhibitors were in contact with helices 11 and 12. Without wishing to be bound by any particular theory, Applicant has observed that the conformation of these helices is generally indicative of whether a compound is acting as an inhibitor, wherein the helices are “compressed” when bound to an agonist, and “disordered” or spread apart when bound to an antagonist. By observing and/or predicting the molecular interactions that would be useful to achieve antagonism, compounds were designed that are antagonists but not agonists. For example, if additional moieties are placed in the correct position, it can result in steric interactions that drive the helices from an agonist conformation into an antagonist conformation. As described herein, chemical syntheses were then be used to validate the predictions. 
     Applicant observed that RU486 and ORN34517 bind GR and AR in the same fashion, and the signature-defining structural moiety of these compounds points toward helix 11 and helix 12. By transposing RU486&#39;s GR binding into AR, Applicant observed that it binds analogously, but does not have the requisite structure to push against helices 11 and 12 to behave as antagonist. Applicant then designed compounds described herein to possess properly-positioned moieties for achieving the desired antagonist activity. Examples of such compounds and moieties are detailed in Appendices C and D, as well as described herein. 
     Example 5: Methods of Identifying Subjects and Monitoring Effects of Therapy 
     Methods of identifying subjects and/or monitoring the effect of therapy in a subject can include obtaining a sample from a subject and performing an analysis on the sample. Methods can also involve taking a plurality of samples over a designated period of time; in some such embodiments, samples are taken are regular intervals during or within the period of time. 
     Many techniques can be used both for identifying subjects and for monitoring the effect of therapy. One such method is to take bone marrow biopsy samples and then use a GR IHC assay optimized for use in bone marrow samples to quantify the percentage of GR-positive tumor cells. Another method is to obtain patient urine samples and test them for prostate cells that are shed during urination. High-throughput proteomics can be used to look at levels of GR or a GR-responsive entity such as SGK1 in serum or urine. Another technique, transcriptome sequencing, can be used to evaluate mRNA levels or GR or a GR-responsive entity such as SGK1. 
     Activation of GR or a GR-responsive entity such as SGK1 can be identified by activation state-specific antibodies that bind to a specific isoform of GR or a GR-responsive entity such as SGK1. One method of measuring activation is via activation state-specific antibodies that are conjugated to a label, preferably a fluorescent label, and more preferably a FRET label. 
     
       
         
           
               
             
               
                   
               
               
                 Sequences 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 SEQ ID NO: 1 Human AR Protein Sequence (GenBank: AAA51729.1) 
               
               
                 MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQ 
               
               
                 QQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAAS 
               
               
                 KGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAR 
               
               
                 EASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPT 
               
               
                 PCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGA 
               
               
                 LDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGP 
               
               
                 GSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLA 
               
               
                 GQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCL 
               
               
                 ICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARK 
               
               
                 LKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAAL 
               
               
                 LSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVF 
               
               
                 NEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDR 
               
               
                 IIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGK 
               
               
                 VKPIYFHTQ 
               
               
                   
               
               
                 SEQ ID NO: 2 Human AR mRNA Sequence (GenBank: M20132.1) 
               
               
                 TAATAACTCAGTTCTTATTTGCACCTACTTCAGTGGACACTGAATTTGGAAGGTGGAGGATTTTGTTTTT 
               
               
                 TTCTTTTAAGATCTGGGCATCTTTTGAATCTACCCTTCAAGTATTAAGAGACAGACTGTGAGCCTAGCAG 
               
               
                 GGCAGATCTTGTCCACCGTGTGTCTTCTTCTGCACGAGACTTTGAGGCTGTCAGAGCGCTTTTTGCGTGG 
               
               
                 TTGCTCCCGCAAGTTTCCTTCTCTGGAGCTTCCCGCAGGTGGGCAGCTAGCTGCAGCGACTACCGCATCA 
               
               
                 TCACAGCCTGTTGAACTCTTCTGAGCAAGAGAAGGGGAGGCGGGGTAAGGGAAGTAGGTGGAAGATTCAG 
               
               
                 CCAAGCTCAAGGATGGAAGTGCAGTTAGGGCTGGGAAGGGTCTACCCTCGGCCGCCGTCCAAGACCTACC 
               
               
                 GAGGAGCTTTCCAGAATCTGTTCCAGAGCGTGCGCGAAGTGATCCAGAACCCGGGCCCCAGGCACCCAGA 
               
               
                 GGCCGCGAGCGCAGCACCTCCCGGCGCCAGTTTGCTGCTGCTGCAGCAGCAGCAGCAGCAGCAGCAGCAG 
               
               
                 CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAAGAGACTAGCCCCAGGCAGCAGCAGCAGCAGCAGG 
               
               
                 GTGAGGATGGTTCTCCCCAAGCCCATCGTAGAGGCCCCACAGGCTACCTGGTCCTGGATGAGGAACAGCA 
               
               
                 ACCTTCACAGCCGCAGTCGGCCCTGGAGTGCCACCCCGAGAGAGGTTGCGTCCCAGAGCCTGGAGCCGCC 
               
               
                 GTGGCCGCCAGCAAGGGGCTGCCGCAGCAGCTGCCAGCACCTCCGGACGAGGATGACTCAGCTGCCCCAT 
               
               
                 CCACGTTGTCCCTGCTGGGCCCCACTTTCCCCGGCTTAAGCAGCTGCTCCGCTGACCTTAAAGACATCCT 
               
               
                 GAGCGAGGCCAGCACCATGCAACTCCTTCAGCAACAGCAGCAGGAAGCAGTATCCGAAGGCAGCAGCAGC 
               
               
                 GGGAGAGCGAGGGAGGCCTCGGGGGCTCCCACTTCCTCCAAGGACAATTACTTAGGGGGCACTTCGACCA 
               
               
                 TTTCTGACAACGCCAAGGAGTTGTGTAAGGCAGTGTCGGTGTCCATGGGCCTGGGTGTGGAGGCGTTGGA 
               
               
                 GCATCTGAGTCCAGGGGAACAGCTTCGGGGGGATTGCATGTACGCCCCACTTTTGGGAGTTCCACCCGCT 
               
               
                 GTGCGTCCCACTCCTTGTGCCCCATTGGCCGAATGCAAAGGTTCTCTGCTAGACGACAGCGCAGGCAAGA 
               
               
                 GCACTGAAGATACTGCTGAGTATTCCCCTTTCAAGGGAGGTTACACCAAAGGGCTAGAAGGCGAGAGCCT 
               
               
                 AGGCTGCTCTGGCAGCGCTGCAGCAGGGAGCTCCGGGACACTTGAACTGCCGTCTACCCTGTCTCTCTAC 
               
               
                 AAGTCCGGAGCACTGGACGAGGCAGCTGCGTACCAGAGTCGCGACTACTACAACTTTCCACTGGCTCTGG 
               
               
                 CCGGACCGCCGCCCCCTCCGCCGCCTCCCCATCCCCACGCTCGCATCAAGCTGGAGAACCCGCTGGACTA 
               
               
                 CGGCAGCGCCTGGGCGGCTGCGGCGGCGCAGTGCCGCTATGGGGACCTGGCGAGCCTGCATGGCGCGGGT 
               
               
                 GCAGCGGGACCCGGTTCTGGGTCACCCTCAGCCGCCGCTTCCTCATCCTGGCACACTCTCTTCACAGCCG 
               
               
                 AAGAAGGCCAGTTGTATGGACCGTGTGGTGGTGGTGGGGGTGGTGGCGGCGGCGGCGGCGGCGGCGGCGG 
               
               
                 CGGCGGCGGCGGCGGCGGCGGCGGCGGCGAGGCGGGAGCTGTAGCCCCCTACGGCTACACTCGGCCCCCT 
               
               
                 CAGGGGCTGGCGGGCCAGGAAAGCGACTTCACCGCACCTGATGTGTGGTACCCTGGCGGCATGGTGAGCA 
               
               
                 GAGTGCCCTATCCCAGTCCCACTTGTGTCAAAAGCGAAATGGGCCCCTGGATGGATAGCTACTCCGGACC 
               
               
                 TTACGGGGACATGCGTTTGGAGACTGCCAGGGACCATGTTTTGCCCATTGACTATTACTTTCCACCCCAG 
               
               
                 AAGACCTGCCTGATCTGTGGAGATGAAGCTTCTGGGTGTCACTATGGAGCTCTCACATGTGGAAGCTGCA 
               
               
                 AGGTCTTCTTCAAAAGAGCCGCTGAAGGGAAACAGAAGTACCTGTGCGCCAGCAGAAATGATTGCACTAT 
               
               
                 TGATAAATTCCGAAGGAAAAATTGTCCATCTTGTCGTCTTCGGAAATGTTATGAAGCAGGGATGACTCTG 
               
               
                 GGAGCCCGGAAGCTGAAGAAACTTGGTAATCTGAAACTACAGGAGGAAGGAGAGGCTTCCAGCACCACCA 
               
               
                 GCCCCACTGAGGAGACAACCCAGAAGCTGACAGTGTCACACATTGAAGGCTATGAATGTCAGCCCATCTT 
               
               
                 TCTGAATGTCCTGGAAGCCATTGAGCCAGGTGTAGTGTGTGCTGGACACGACAACAACCAGCCCGACTCC 
               
               
                 TTTGCAGCCTTGCTCTCTAGCCTCAATGAACTGGGAGAGAGACAGCTTGTACACGTGGTCAAGTGGGCCA 
               
               
                 AGGCCTTGCCTGGCTTCCGCAACTTACACGTGGACGACCAGATGGCTGTCATTCAGTACTCCTGGATGGG 
               
               
                 GCTCATGGTGTTTGCCATGGGCTGGCGATCCTTCACCAATGTCAACTCCAGGATGCTCTACTTCGCCCCT 
               
               
                 GATCTGGTTTTCAATGAGTACCGCATGCACAAGTCCCGGATGTACAGCCAGTGTGTCCGAATGAGGCACC 
               
               
                 TCTCTCAAGAGTTTGGATGGCTCCAAATCACCCCCCAGGAATTCCTGTGCATGAAAGCACTGCTACTCTT 
               
               
                 CAGCATTATTCCAGTGGATGGGCTGAAAAATCAAAAATTCTTTGATGAACTTCGAATGAACTACATCAAG 
               
               
                 GAACTCGATCGTATCATTGCATGCAAAAGAAAAAATCCCACATCCTGCTCAAGACGCTTCTACCAGCTCA 
               
               
                 CCAAGCTCCTGGACTCCGTGCAGCCTATTGCGAGAGAGCTGCATCAGTTCACTTTTGACCTGCTAATCAA 
               
               
                 GTCACACATGGTGAGCGTGGACTTTCCGGAAATGATGGCAGAGATCATCTCTGTGCAAGTGCCCAAGATC 
               
               
                 CTTTCTGGGAAAGTCAAGCCCATCTATTTCCACACCCAGTGAAGCATTGGAAACCCTATTTCCCCACCCC 
               
               
                 AGCTCATGCCCCCTTTCAGATGTCTTCTGCCTGTTATAACTCTGCACTACTCCTCTGCAGTGCCTTGGGG 
               
               
                 AATTTCCTCTATTGATGTACAGTCTGTCATGAACATGTTCCTGAATTCTATTTGCTGGGCTTTTTTTTTC 
               
               
                 TCTTTCTCTCCTTTCTTTTTCTTCTTCCCTCCCTATCTAACCCTCCCATGGCACCTTCAGACTTTGCTTC 
               
               
                 CCATTGTGGCTCCTATCTGTGTTTTGAATGGTGTTGTATGCCTTTAAATCTGTGATGATCCTCATATGGC 
               
               
                 CCAGTGTCAAGTTGTGCTTGTTTACAGCACTACTCTGTGCCAGCCACACAAACGTTTACTTATCTTATGC 
               
               
                 CACGGGAAGTTTAGAGAGCTAAGATTATCTGGGGAAATCAAAACAAAAAACAAGCAAACAAAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 3 Human GR Isoform alpha Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001018086.1) 
               
               
                 MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRRLLVDFPKGSV 
               
               
                 SNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPK 
               
               
                 SSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTEDILQDLEFSSGSPGKETNE 
               
               
                 SPWRSDLLIDENCLLSPLAGEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEK 
               
               
                 EDFIELCTPGVIKQEKLGTVYCQASFPGANTIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPI 
               
               
                 FNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL 
               
               
                 CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEA 
               
               
                 RKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIM 
               
               
                 TTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIIN 
               
               
                 EQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKA 
               
               
                 IVKREGNSSQNWQRFYQLTKLLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIK 
               
               
                 KLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 4 Human GR Isoform alpha-B Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191187.1) 
               
               
                 MDFYKTLRGGATVKVSASSPSLAVASQSDSKQRRLLVDFPKGSVSNAQQPDLSKAVSLSMGLYMGETETK 
               
               
                 VMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSE 
               
               
                 QQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFL 
               
               
                 LEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGTVYCQASF 
               
               
                 PGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQGSGDDNLT 
               
               
                 SLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFK 
               
               
                 RAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPG 
               
               
                 NKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRN 
               
               
                 LHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRL 
               
               
                 QVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMH 
               
               
                 EVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 5 Human GR Isoform alpha-C1 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191188.1) 
               
               
                 MGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPKSSASTAVSAAPTEKE 
               
               
                 FPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLL 
               
               
                 SPLAGEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQE 
               
               
                 KLGTVYCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWN 
               
               
                 RCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGV 
               
               
                 LTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATT 
               
               
                 GVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAV 
               
               
                 KWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKH 
               
               
                 MLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRF 
               
               
                 YQLTKLLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 6 Human GR Isoform alpha-C2 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191187.1) 
               
               
                 MGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKT 
               
               
                 HSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLA 
               
               
                 GEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGT 
               
               
                 VYCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQG 
               
               
                 SGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCG 
               
               
                 SCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQ 
               
               
                 ETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAK 
               
               
                 AIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYV 
               
               
                 SSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLT 
               
               
                 KLLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 7 Human GR Isoform alpha-C3 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191190.1) 
               
               
                 MGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPKSSASTAVSAAPTEKEFPKTHSDVSSEQ 
               
               
                 QHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNESPWRSDLLIDENCLLSPLAGEDDSFLL 
               
               
                 EGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEKEDFIELCTPGVIKQEKLGTVYCQASFP 
               
               
                 GANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQGSGDDNLTS 
               
               
                 LGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFKR 
               
               
                 AVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGN 
               
               
                 KTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNL 
               
               
                 HLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQ 
               
               
                 VSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMHE 
               
               
                 VVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 8 Human GR Isoform alpha-D1 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191191.1) 
               
               
                 MSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPG 
               
               
                 RTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNY 
               
               
                 LCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATL 
               
               
                 PQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTL 
               
               
                 LQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLC 
               
               
                 MKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMHEVVENLLNY 
               
               
                 CFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 9 Human GR Isoform alpha-D2 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191192.1) 
               
               
                 MYHYDMNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRP 
               
               
                 DVSSPPSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRR 
               
               
                 KNCPACRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIE 
               
               
                 PEVLYAGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGW 
               
               
                 RSYRQSSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGL 
               
               
                 KSQELFDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMHEVVENLLNYCFQTFLDKTMSIEFP 
               
               
                 EMLAEIITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 10 Human GR Isoform alpha-D3 Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191193.1) 
               
               
                 MNTASLSQQQDQKPIFNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSP 
               
               
                 PSSSSTATTGPPPKLCLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPA 
               
               
                 CRYRKCLQAGMNLEARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLY 
               
               
                 AGYDSSVPDSTWRIMTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQ 
               
               
                 SSANLLCFAPDLIINEQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQEL 
               
               
                 FDEIRMTYIKELGKAIVKREGNSSQNWQRFYQLTKLLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAE 
               
               
                 IITNQIPKYSNGNIKKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 11 Human GR Isoform GR-PProtein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001191193.1) 
               
               
                 MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRRLLVDFPKGSV 
               
               
                 SNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPK 
               
               
                 SSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNE 
               
               
                 SPWRSDLLIDENCLLSPLAGEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEK 
               
               
                 EDFIELCTPGVIKQEKLGTVYCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPI 
               
               
                 FNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL 
               
               
                 CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEA 
               
               
                 RKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIM 
               
               
                 TTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIIN 
               
               
                 EQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSGW 
               
               
                   
               
               
                 SEQ ID NO: 12 Human GR Isoform gamma Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001018086.1) 
               
               
                 MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRRLLVDFPKGSV 
               
               
                 SNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPK 
               
               
                 SSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNE 
               
               
                 SPWRSDLLIDENCLLSPLAGEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEK 
               
               
                 EDFIELCTPGVIKQEKLGTVYCQASFPGANIIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPI 
               
               
                 FNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL 
               
               
                 CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGRQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLE 
               
               
                 ARKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRI 
               
               
                 MTTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLII 
               
               
                 NEQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGK 
               
               
                 AIVKREGNSSQNWQRFYQLTKLLDSMHEVVENLLNYCFQTFLDKTMSIEFPEMLAEIITNQIPKYSNGNI 
               
               
                 KKLLFHQK 
               
               
                   
               
               
                 SEQ ID NO: 13 Human GR Isoform beta Protein Sequence (NCBI Reference Sequence: 
               
               
                 NP_001018661.1) 
               
               
                 MDSKESLTPGREENPSSVLAQERGDVMDFYKTLRGGATVKVSASSPSLAVASQSDSKQRRLLVDFPKGSV 
               
               
                 SNAQQPDLSKAVSLSMGLYMGETETKVMGNDLGFPQQGQISLSSGETDLKLLEESIANLNRSTSVPENPK 
               
               
                 SSASTAVSAAPTEKEFPKTHSDVSSEQQHLKGQTGTNGGNVKLYTTDQSTFDILQDLEFSSGSPGKETNE 
               
               
                 SPWRSDLLIDENCLLSPLAGEDDSFLLEGNSNEDCKPLILPDTKPKIKDNGDLVLSSPSNVTLPQVKTEK 
               
               
                 EDFIELCTPGVIKQEKLGTVYCQASFPGANTIGNKMSAISVHGVSTSGGQMYHYDMNTASLSQQQDQKPI 
               
               
                 FNVIPPIPVGSENWNRCQGSGDDNLTSLGTLNFPGRTVFSNGYSSPSMRPDVSSPPSSSSTATTGPPPKL 
               
               
                 CLVCSDEASGCHYGVLTCGSCKVFFKRAVEGQHNYLCAGRNDCIIDKIRRKNCPACRYRKCLQAGMNLEA 
               
               
                 RKTKKKIKGIQQATTGVSQETSENPGNKTIVPATLPQLTPTLVSLLEVIEPEVLYAGYDSSVPDSTWRIM 
               
               
                 TTLNMLGGRQVIAAVKWAKAIPGFRNLHLDDQMTLLQYSWMFLMAFALGWRSYRQSSANLLCFAPDLIIN 
               
               
                 EQRMTLPCMYDQCKHMLYVSSELHRLQVSYEEYLCMKTLLLLSSVPKDGLKSQELFDEIRMTYIKELGKA 
               
               
                 IVKREGNSSQNWQRFYQLTKLLDSMHENVMWLKPESTSHTLI 
               
               
                   
               
               
                 SEQ ID NO: 14 Human GR Transcript Variant 1 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001204259.1) 
               
               
                 GGCGCCGCCTCCACCCGCTCCCCGCTCGGTCCCGCTCGCTCGCCCAGGCCGGGCTGCCCTTTCGCGTGTC 
               
               
                 CGCGCTCTCTTCCCTCCGCCGCCGCCTCCTCCATTTTGCGAGCTCGTGTCTGTGACGGGAGCCCGAGTCA 
               
               
                 CCGCCTGCCCGTCGGGGACGGATTCTGTGGGTGGAAGGAGACGCCGCAGCCGGAGCGGCCGAAGCAGCTG 
               
               
                 GGACCGGGACGGGGCACGCGCGCCCGGAACCTCGACCCGCGGAGCCCGGCGCGGGGCGGAGGGCTGGCTT 
               
               
                 GTCAGCTGGGCAATGGGAGACTTTCTTAAATAGGGGCTCTCCCCCCACCCATGGAGAAAGGGGCGGCTGT 
               
               
                 TTACTTCCTTTTTTTAGAAAAAAAAAATATATTTCCCTCCTGCTCCTTCTGCGTTCACAAGCTAAGTTGT 
               
               
                 TTATCTCGGCTGCGGCGGGAACTGCGGACGGTGGCGGGCGAGCGGCTCCTCTGCCAGAGTTGATATTCAC 
               
               
                 TGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAG 
               
               
                 GGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCC 
               
               
                 TCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAG 
               
               
                 TAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGAC 
               
               
                 AGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAA 
               
               
                 ACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCA 
               
               
                 AGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGT 
               
               
                 ATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACA 
               
               
                 GACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATG 
               
               
                 AGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGA 
               
               
                 TTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAA 
               
               
                 ATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAA 
               
               
                 AAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCA 
               
               
                 GGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACC 
               
               
                 TCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTA 
               
               
                 TTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGA 
               
               
                 CAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCC 
               
               
                 AGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAAC 
               
               
                 TCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGT 
               
               
                 TTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGGAAGGAATGATTGCATCATCGAT 
               
               
                 AAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGGAAG 
               
               
                 CTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGA 
               
               
                 AAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTG 
               
               
                 GAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGATCA 
               
               
                 TGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACCAGG 
               
               
                 TTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCATTT 
               
               
                 GCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTA 
               
               
                 ATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAGTT 
               
               
                 ACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGTTCCT 
               
               
                 AAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAATGACCTACATCAAAGAGCTAGGAAAAG 
               
               
                 CCATTGTCAAGAGGGAAGGAAACTCCAGCCAGAACTGGCAGCGGTTTTATCAACTGACAAAACTCTTGGA 
               
               
                 TTCTATGCATGAAGTGGTTGAAAATCTCCTTAACTATTGCTTCCAAACATTTTTGGATAAGACCATGAGT 
               
               
                 ATTGAATTCCCCGAGATGTTAGCTGAAATCATCACCAATCAGATACCAAAATATTCAAATGGAAATATCA 
               
               
                 AAAAACTTCTGTTTCATCAAAAGTGACTGCCTTAATAAGAATGGTTGCCTTAAAGAAAGTCGAATTAATA 
               
               
                 GCTTTTATTGTATAAACTATCAGTTTGTCCTGTAGAGGTTTTGTTGTTTTATTTTTTATTGTTTTCATCT 
               
               
                 GTTGTTTTGTTTTAAATACGCACTACATGTGGTTTATAGAGGGCCAAGACTTGGCAACAGAAGCAGTTGA 
               
               
                 GTCGTCATCACTTTTCAGTGATGGGAGAGTAGATGGTGAAATTTATTAGTTAATATATCCCAGAAATTAG 
               
               
                 AAACCTTAATATGTGGACGTAATCTCCACAGTCAAAGAAGGATGGCACCTAAACCACCAGTGCCCAAAGT 
               
               
                 CTGTGTGATGAACTTTCTCTTCATACTTTTTTTCACAGTTGGCTGGATGAAATTTTCTAGACTTTCTGTT 
               
               
                 GGTGTATCCCCCCCCTGTATAGTTAGGATAGCATTTTTGATTTATGCATGGAAACCTGAAAAAAAGTTTA 
               
               
                 CAAGTGTATATCAGAAAAGGGAAGTTGTGCCTTTTATAGCTATTACTGTCTGGTTTTAACAATTTCCTTT 
               
               
                 ATATTTAGTGAACTACGCTTGCTCATTTTTTCTTACATAATTTTTTATTCAAGTTATTGTACAGCTGTTT 
               
               
                 AAGATGGGCAGCTAGTTCGTAGCTTTCCCAAATAAACTCTAAACATTAATCAATCATCTGTGTGAAAATG 
               
               
                 GGTTGGTGCTTCTAACCTGATGGCACTTAGCTATCAGAAGACCACAAAAATTGACTCAAATCTCCAGTAT 
               
               
                 TCTTGTCAAAAAAAAAAAAAAAAAAGCTCATATTTTGTATATATCTGCTTCAGTGGAGAATTATATAGGT 
               
               
                 TGTGCAAATTAACAGTCCTAACTGGTATAGAGCACCTAGTCCAGTGACCTGCTGGGTAAACTGTGGATGA 
               
               
                 TGGTTGCAAAAGACTAATTTAAAAAATAACTACCAAGAGGCCCTGTCTGTACCTAACGCCCTATTTTTGC 
               
               
                 AATGGCTATATGGCAAGAAAGCTGGTAAACTATTTGTCTTTCAGGACCTTTTGAAGTAGTTTGTATAACT 
               
               
                 TCTTAAAAGTTGTGATTCCAGATAACCAGCTGTAACACAGCTGAGAGACTTTTAATCAGACAAAGTAATT 
               
               
                 CCTCTCACTAAACTTTACCCAAAAACTAAATCTCTAATATGGCAAAAATGGCTAGACACCCATTTTCACA 
               
               
                 TTCCCATCTGTCACCAATTGGTTAATCTTTCCTGATGGTACAGGAAAGCTCAGCTACTGATTTTTGTGAT 
               
               
                 TTAGAACTGTATGTCAGACATCCATGTTTGTAAAACTACACATCCCTAATGTGTGCCATAGAGTTTAACA 
               
               
                 CAAGTCCTGTGAATTTCTTCACTGTTGAAAATTATTTTAAACAAAATAGAAGCTGTAGTAGCCCTTTCTG 
               
               
                 TGTGCACCTTACCAACTTTCTGTAAACTCAAAACTTAACATATTTACTAAGCCACAAGAAATTTGATTTC 
               
               
                 TATTCAAGGTGGCCAAATTATTTGTGTAATAGAAAACTGAAAATCTAATATTAAAAATATGGAACTTCTA 
               
               
                 ATATATTTTTATATTTAGTTATAGTTTCAGATATATATCATATTGGTATTCACTAATCTGGGAAGGGAAG 
               
               
                 GGCTACTGCAGCTTTACATGCAATTTATTAAAATGATTGTAAAATAGCTTGTATAGTGTAAAATAAGAAT 
               
               
                 GATTTTTAGATGAGATTGTTTTATCATGACATGTTATATATTTTTTGTAGGGGTCAAAGAAATGCTGATG 
               
               
                 GATAACCTATATGATTTATAGTTTGTACATGCATTCATACAGGCAGCGATGGTCTCAGAAACCAAACAGT 
               
               
                 TTGCTCTAGGGGAAGAGGGAGATGGAGACTGGTCCTGTGTGCAGTGAAGGTTGCTGAGGCTCTGACCCAG 
               
               
                 TGAGATTACAGAGGAAGTTATCCTCTGCCTCCCATTCTGACCACCCTTCTCATTCCAACAGTGAGTCTGT 
               
               
                 CAGCGCAGGTTTAGTTTACTCAATCTCCCCTTGCACTAAAGTATGTAAAGTATGTAAACAGGAGACAGGA 
               
               
                 AGGTGGTGCTTACATCCTTAAAGGCACCATCTAATAGCGGGTTACTTTCACATACAGCCCTCCCCCAGCA 
               
               
                 GTTGAATGACAACAGAAGCTTCAGAAGTTTGGCAATAGTTTGCATAGAGGTACCAGCAATATGTAAATAG 
               
               
                 TGCAGAATCTCATAGGTTGCCAATAATACACTAATTCCTTTCTATCCTACAACAAGAGTTTATTTCCAAA 
               
               
                 TAAAATGAGGACATGTTTTTGTTTTCTTTGAATGCTTTTTGAATGTTATTTGTTATTTTCAGTATTTTGG 
               
               
                 AGAAATTATTTAATAAAAAAACAATCATTTGCTTTTTGAATGCTCTCTAAAAGGGAATGTAATATTTTAA 
               
               
                 GATGGTGTGTAACCCGGCTGGATAAATTTTTGGTGCCTAAGAAAACTGCTTGAATATTCTTATCAATGAC 
               
               
                 AGTGTTAAGTTTCAAAAAGAGCTTCTAAAACGTAGATTATCATTCCTTTATAGAATGTTATGTGGTTAAA 
               
               
                 ACCAGAAAGCACATCTCACACATTAATCTGATTTTCATCCCAACAATCTTGGCGCTCAAAAAATAGAACT 
               
               
                 CAATGAGAAAAAGAAGATTATGTGCACTTCGTTGTCAATAATAAGTCAACTGATGCTCATCGACAACTAT 
               
               
                 AGGAGGCTTTTCATTAAATGGGAAAAGAAGCTGTGCCCTTTTAGGATACGTGGGGGAAAAGAAAGTCATC 
               
               
                 TTAATTATGTTTAATTGTGGATTTAAGTGCTATATGGTGGTGCTGTTTGAAAGCAGATTTATTTCCTATG 
               
               
                 TATGTGTTATCTGGCCATCCCAACCCAAACTGTTGAAGTTTGTAGTAACTTCAGTGAGAGTTGGTTACTC 
               
               
                 ACAACAAATCCTGAAAAGTATTTTTAGTGTTTGTAGGTATTCTGTGGGATACTATACAAGCAGAACTGAG 
               
               
                 GCACTTAGGACATAACACTTTTGGGGTATATATATCCAAATGCCTAAAACTATGGGAGGAAACCTTGGCC 
               
               
                 ACCCCAAAAGGAAAACTAACATGATTTGTGTCTATGAAGTGCTGGATAATTAGCATGGGATGAGCTCTGG 
               
               
                 GCATGCCATGAAGGAAAGCCACGCTCCCTTCAGAATTCAGAGGCAGGGAGCAATTCCAGTTTCACCTAAG 
               
               
                 TCTCATAATTTTAGTTCCCTTTTAAAAACCCTGAAAACTACATCACCATGGAATGAAAAATATTGTTATA 
               
               
                 CAATACATTGATCTGTCAAACTTCCAGAACCATGGTAGCCTTCAGTGAGATTTCCATCTTGGCTGGTCAC 
               
               
                 TCCCTGACTGTAGCTGTAGGTGAATGTGTTTTTGTGTGTGTGTGTCTGGTTTTAGTGTCAGAAGGGAAAT 
               
               
                 AAAAGTGTAAGGAGGACACTTTAAACCCTTTGGGTGGAGTTTCGTAATTTCCCAGACTATTTTCAAGCAA 
               
               
                 CCTGGTCCACCCAGGATTAGTGACCAGGTTTTCAGGAAAGGATTTGCTTCTCTCTAGAAAATGTCTGAAA 
               
               
                 GGATTTTATTTTCTGATGAAAGGCTGTATGAAAATACCCTCCTCAAATAACTTGCTTAACTACATATAGA 
               
               
                 TTCAAGTGTGTCAATATTCTATTTTGTATATTAAATGCTATATAATGGGGACAAATCTATATTATACTGT 
               
               
                 GTATGGCATTATTAAGAAGCTTTTTCATTATTTTTTATCACAGTAATTTTAAAATGTGTAAAAATTAAAA 
               
               
                 CCAGTGACTCCTGTTTAAAAATAAAAGTTGTAGTTTTTTATTCATGCTGAATAATAATCTGTAGTTAAAA 
               
               
                 AAAAAGTGTCTTTTTACCTACGCAGTGAAATGTCAGACTGTAAAACCTTGTGTGGAAATGTTTAACTTTT 
               
               
                 ATTTTTTCATTTAAATTTGCTGTTCTGGTATTACCAAACCACACATTTGTACCGAATTGGCAGTAAATGT 
               
               
                 TAGCCATTTACAGCAATGCCAAATATGGAGAAACATCATAATAAAAAAATCTGCTTTTTCATTAAAAAAA 
               
               
                 AAAAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 15 Human GR Transcript Variant 2 mRNA Sequence (NCBI Reference Sequence 
               
               
                 NM_001018074.1) 
               
               
                 AGGTTATGTAAGGGTTTGCTTTCACCCCATTCAAAAGGTACCTCTTCCTCTTCTCTTGCTCCCTCTCGCC 
               
               
                 CTCATTCTTGTGCCTATGCAGACATTTGAGTAGAGGCGAATCACTTTCACTTCTGCTGGGGAAATTGCAA 
               
               
                 CACGCTTCTTTAAATGGCAGAGAGAAGGAGAAAACTTAGATCTTCTGATACCAAATCACTGGACCTTAGA 
               
               
                 AGGTCAGAAATCTTTCAAGCCCTGCAGGACCGTAAAATGCGCATGTGTCCAACGGAAGCACTGGGGCATG 
               
               
                 AGTGGGGAAGGAATAGAAACAGAAAGAGGTTGATATTCACTGATGGACTCCAAAGAATCATTAACTCCTG 
               
               
                 GTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAGGGGAGATGTGATGGACTTCTATAAAACCCT 
               
               
                 AAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCCTCACTGGCTGTCGCTTCTCAATCAGACTCC 
               
               
                 AAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAGTAAGCAATGCGCAGCAGCCAGATCTGTCCA 
               
               
                 AAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGACAGAAACAAAAGTGATGGGAAATGACCTGGG 
               
               
                 ATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAAACAGACTTAAAGCTTTTGGAAGAAAGCATT 
               
               
                 GCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCAAGAGTTCAGCATCCACTGCTGTGTCTGCTG 
               
               
                 CCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGTATCTTCAGAACAGCAACATTTGAAGGGCCA 
               
               
                 GACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACAGACCAAAGCACCTTTGACATTTTGCAGGAT 
               
               
                 TTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATGAGAGTCCTTGGAGATCAGACCTGTTGATAG 
               
               
                 ATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGATTCATTCCTTTTGGAAGGAAACTCGAATGA 
               
               
                 GGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAAATTAAGGATAATGGAGATCTGGTTTTGTCA 
               
               
                 AGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAAAAGAAGATTTCATCGAACTCTGCACCCCTG 
               
               
                 GGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCAGGCAAGCTTTCCTGGAGCAAATATAATTGG 
               
               
                 TAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACCTCTGGAGGACAGATGTACCACTATGACATG 
               
               
                 AATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTATTTTTAATGTCATTCCACCAATTCCCGTTG 
               
               
                 GTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGACAACTTGACTTCTCTGGGGACTCTGAACTT 
               
               
                 CCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCCAGCATGAGACCAGATGTAAGCTCTCCTCCA 
               
               
                 TCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAACTCTGCCTGGTGTGCTCTGATGAAGCTTCAG 
               
               
                 GATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGTTTTCTTCAAAAGAGCAGTGGAAGGACAGCA 
               
               
                 CAATTACCTATGTGCTGGAAGGAATGATTGCATCATCGATAAAATTCGAAGAAAAAACTGCCCAGCATGC 
               
               
                 CGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGGAAGCTCGAAAAACAAAGAAAAAAATAAAAGGAA 
               
               
                 TTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGAAAATCCTGGTAACAAAACAATAGTTCCTGC 
               
               
                 AACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTGGAGGTTATTGAACCTGAAGTGTTATATGCA 
               
               
                 GGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGATCATGACTACGCTCAACATGTTAGGAGGGCGGC 
               
               
                 AAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACCAGGTTTCAGGAACTTACACCTGGATGACCAAAT 
               
               
                 GACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCATTTGCTCTGGGGTGGAGATCATATAGACAATCA 
               
               
                 AGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTAATGAGCAGAGAATGACTCTACCCTGCATGT 
               
               
                 ACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAGTTACACAGGCTTCAGGTATCTTATGAAGAGTA 
               
               
                 TCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGTTCCTAAGGACGGTCTGAAGAGCCAAGAGCTATTT 
               
               
                 GATGAAATTAGAATGACCTACATCAAAGAGCTAGGAAAAGCCATTGTCAAGAGGGAAGGAAACTCCAGCC 
               
               
                 AGAACTGGCAGCGGTTTTATCAACTGACAAAACTCTTGGATTCTATGCATGAAGTGGTTGAAAATCTCCT 
               
               
                 TAACTATTGCTTCCAAACATTTTTGGATAAGACCATGAGTATTGAATTCCCCGAGATGTTAGCTGAAATC 
               
               
                 ATCACCAATCAGATACCAAAATATTCAAATGGAAATATCAAAAAACTTCTGTTTCATCAAAAGTGACTGC 
               
               
                 CTTAATAAGAATGGTTGCCTTAAAGAAAGTCGAATTAATAGCTTTTATTGTATAAACTATCAGTTTGTCC 
               
               
                 TGTAGAGGTTTTGTTGTTTTATTTTTTATTGTTTTCATCTGTTGTTTTGTTTTAAATACGCACTACATGT 
               
               
                 GGTTTATAGAGGGCCAAGACTTGGCAACAGAAGCAGTTGAGTCGTCATCACTTTTCAGTGATGGGAGAGT 
               
               
                 AGATGGTGAAATTTATTAGTTAATATATCCCAGAAATTAGAAACCTTAATATGTGGACGTAATCTCCACA 
               
               
                 GTCAAAGAAGGATGGCACCTAAACCACCAGTGCCCAAAGTCTGTGTGATGAACTTTCTCTTCATACTTTT 
               
               
                 TTTCACAGTTGGCTGGATGAAATTTTCTAGACTTTCTGTTGGTGTATCCCCCCCCTGTATAGTTAGGATA 
               
               
                 GCATTTTTGATTTATGCATGGAAACCTGAAAAAAAGTTTACAAGTGTATATCAGAAAAGGGAAGTTGTGC 
               
               
                 CTTTTATAGCTATTACTGTCTGGTTTTAACAATTTCCTTTATATTTAGTGAACTACGCTTGCTCATTTTT 
               
               
                 TCTTACATAATTTTTTATTCAAGTTATTGTACAGCTGTTTAAGATGGGCAGCTAGTTCGTAGCTTTCCCA 
               
               
                 AATAAACTCTAAACATTAATCAATCATCTGTGTGAAAATGGGTTGGTGCTTCTAACCTGATGGCACTTAG 
               
               
                 CTATCAGAAGACCACAAATTGACTCAAATCTCCAGTATTCTTGTCAAAAAAAAAAAAAAAAAAAAGCTCA 
               
               
                 TATTTTGTATATATCTGCTTCAGTGGAGAATTATATAGGTTGTGCAAATTAACAGTCCTAACTGGTATAG 
               
               
                 AGCACCTAGTCCAGTGACCTGCTGGGTAAACTGTGGATGATGGTTGCAAAAGACTAATTTAAAAAATAAC 
               
               
                 TACCAAGAGGCCCTGTCTGTACCTAACGCCCTATTTTTGCAATGGCTATATGGCAAGAAAGCTGGTAAAC 
               
               
                 TATTTGTCTTTCAGGACCTTTTGAAGTAGTTTGTATAACTTCTTAAAAGTTGTGATTCCAGATAACCAGC 
               
               
                 TGTAACACAGCTGAGAGACTTTTAATCAGACAAAGTAATTCCTCTCACTAAACTTTACCCAAAAACTAAA 
               
               
                 TCTCTAATATGGCAAAAATGGCTAGACACCCATTTTCACATTCCCATCTGTCACCAATTGGTTAATCTTT 
               
               
                 CCTGATGGTACAGGAAAGCTCAGCTACTGATTTTTGTGATTTAGAACTGTATGTCAGACATCCATGTTTG 
               
               
                 TAAAACTACACATCCCTAATGTGTGCCATAGAGTTTAACACAAGTCCTGTGAATTTCTTCACTGTTGAAA 
               
               
                 ATTATTTTAAACAAAATAGAAGCTGTAGTAGCCCTTTCTGTGTGCACCTTACCAACTTTCTGTAAACTCA 
               
               
                 AAACTTAACATATTTACTAAGCCACAAGAAATTTGATTTCTATTCAAGGTGGCCAAATTATTTGTGTAAT 
               
               
                 AGAAAACTGAAAATCTAATATTAAAAATATGGAACTTCTAATATATTTTTATATTTAGTTATAGTTTCAG 
               
               
                 ATATATATCATATTGGTATTCACTAATCTGGGAAGGGAAGGGCTACTGCAGCTTTACATGCAATTTATTA 
               
               
                 AAATGATTGTAAAATAGCTTGTATAGTGTAAAATAAGAATGATTTTTAGATGAGATTGTTTTATCATGAC 
               
               
                 ATGTTATATATTTTTTGTAGGGGTCAAAGAAATGCTGATGGATAACCTATATGATTTATAGTTTGTACAT 
               
               
                 GCATTCATACAGGCAGCGATGGTCTCAGAAACCAAACAGTTTGCTCTAGGGGAAGAGGGAGATGGAGACT 
               
               
                 GGTCCTGTGTGCAGTGAAGGTTGCTGAGGCTCTGACCCAGTGAGATTACAGAGGAAGTTATCCTCTGCCT 
               
               
                 CCCATTCTGACCACCCTTCTCATTCCAACAGTGAGTCTGTCAGCGCAGGTTTAGTTTACTCAATCTCCCC 
               
               
                 TTGCACTAAAGTATGTAAAGTATGTAAACAGGAGACAGGAAGGTGGTGCTTACATCCTTAAAGGCACCAT 
               
               
                 CTAATAGCGGGTTACTTTCACATACAGCCCTCCCCCAGCAGTTGAATGACAACAGAAGCTTCAGAAGTTT 
               
               
                 GGCAATAGTTTGCATAGAGGTACCAGCAATATGTAAATAGTGCAGAATCTCATAGGTTGCCAATAATACA 
               
               
                 CTAATTCCTTTCTATCCTACAACAAGAGTTTATTTCCAAATAAAATGAGGACATGTTTTTGTTTTCTTTG 
               
               
                 AATGCTTTTTGAATGTTATTTGTTATTTTCAGTATTTTGGAGAAATTATTTAATAAAAAAACAATCATTT 
               
               
                 GCTTTTTGAATGCTCTCTAAAAGGGAATGTAATATTTTAAGATGGTGTGTAACCCGGCTGGATAAATTTT 
               
               
                 TGGTGCCTAAGAAAACTGCTTGAATATTCTTATCAATGACAGTGTTAAGTTTCAAAAAGAGCTTCTAAAA 
               
               
                 CGTAGATTATCATTCCTTTATAGAATGTTATGTGGTTAAAACCAGAAAGCACATCTCACACATTAATCTG 
               
               
                 ATTTTCATCCCAACAATCTTGGCGCTCAAAAAATAGAACTCAATGAGAAAAAGAAGATTATGTGCACTTC 
               
               
                 GTTGTCAATAATAAGTCAACTGATGCTCATCGACAACTATAGGAGGCTTTTCATTAAATGGGAAAAGAAG 
               
               
                 CTGTGCCCTTTTAGGATACGTGGGGGAAAAGAAAGTCATCTTAATTATGTTTAATTGTGGATTTAAGTGC 
               
               
                 TATATGGTGGTGCTGTTTGAAAGCAGATTTATTTCCTATGTATGTGTTATCTGGCCATCCCAACCCAAAC 
               
               
                 TGTTGAAGTTTGTAGTAACTTCAGTGAGAGTTGGTTACTCACAACAAATCCTGAAAAGTATTTTTAGTGT 
               
               
                 TTGTAGGTATTCTGTGGGATACTATACAAGCAGAACTGAGGCACTTAGGACATAACACTTTTGGGGTATA 
               
               
                 TATATCCAAATGCCTAAAACTATGGGAGGAAACCTTGGCCACCCCAAAAGGAAAACTAACATGATTTGTG 
               
               
                 TCTATGAAGTGCTGGATAATTAGCATGGGATGAGCTCTGGGCATGCCATGAAGGAAAGCCACGCTCCCTT 
               
               
                 CAGAATTCAGAGGCAGGGAGCAATTCCAGTTTCACCTAAGTCTCATAATTTTAGTTCCCTTTTAAAAACC 
               
               
                 CTGAAAACTACATCACCATGGAATGAAAAATATTGTTATACAATACATTGATCTGTCAAACTTCCAGAAC 
               
               
                 CATGGTAGCCTTCAGTGAGATTTCCATCTTGGCTGGTCACTCCCTGACTGTAGCTGTAGGTGAATGTGTT 
               
               
                 TTTGTGTGTGTGTGTCTGGTTTTAGTGTCAGAAGGGAAATAAAAGTGTAAGGAGGACACTTTAAACCCTT 
               
               
                 TGGGTGGAGTTTCGTAATTTCCCAGACTATTTTCAAGCAACCTGGTCCACCCAGGATTAGTGACCAGGTT 
               
               
                 TTCAGGAAAGGATTTGCTTCTCTCTAGAAAATGTCTGAAAGGATTTTATTTTCTGATGAAAGGCTGTATG 
               
               
                 AAAATACCCTCCTCAAATAACTTGCTTAACTACATATAGATTCAAGTGTGTCAATATTCTATTTTGTATA 
               
               
                 TTAAATGCTATATAATGGGGACAAATCTATATTATACTGTGTATGGCATTATTAAGAAGCTTTTTCATTA 
               
               
                 TTTTTTATCACAGTAATTTTAAAATGTGTAAAAATTAAAACCAGTGACTCCTGTTTAAAAATAAAAGTTG 
               
               
                 TAGTTTTTTATTCATGCTGAATAATAATCTGTAGTTAAAAAAAAAGTGTCTTTTTACCTACGCAGTGAAA 
               
               
                 TGTCAGACTGTAAAACCTTGTGTGGAAATGTTTAACTTTTATTTTTTCATTTAAATTTGCTGTTCTGGTA 
               
               
                 TTACCAAACCACACATTTGTACCGAATTGGCAGTAAATGTTAGCCATTTACAGCAATGCCAAATATGGAG 
               
               
                 AAACATCATAATAAAAAAATCTGCTTTTTCATTA 
               
               
                   
               
               
                 SEQ ID NO: 16 Human GR Transcript Variant 3 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001018075.1) 
               
               
                 AGGTTATGTAAGGGTTTGCTTTCACCCCATTCAAAAGGTACCTCTTCCTCTTCTCTTGCTCCCTCTCGCC 
               
               
                 CTCATTCTTGTGCCTATGCAGACATTTGAGTAGAGGCGAATCACTTTCACTTCTGCTGGGGAAATTGCAA 
               
               
                 CACGCTTCTTTAAATGGCAGAGAGAAGGAGAAAACTTAGATCTTCTGATACCAAATCACTGGACCTTAGA 
               
               
                 AGTTGATATTCACTGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGC 
               
               
                 TTGCTCAGGAGAGGGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTC 
               
               
                 TGCGTCTTCACCCTCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTT 
               
               
                 CCAAAAGGCTCAGTAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGT 
               
               
                 ATATGGGAGAGACAGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCT 
               
               
                 TTCCTCGGGGGAAACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTT 
               
               
                 CCAGAGAACCCCAAGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAA 
               
               
                 CTCACTCTGATGTATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAA 
               
               
                 ATTGTATACCACAGACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGT 
               
               
                 AAAGAGACGAATGAGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGG 
               
               
                 CGGGAGAAGACGATTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGA 
               
               
                 CACTAAACCCAAAATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAA 
               
               
                 GTGAAAACAGAAAAAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCA 
               
               
                 CAGTTTACTGTCAGGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCA 
               
               
                 TGGTGTGAGTACCTCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAG 
               
               
                 GATCAGAAGCCTATTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAG 
               
               
                 GATCTGGAGATGACAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGG 
               
               
                 CTATTCAAGCCCCAGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGA 
               
               
                 CCACCTCCCAAACTCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTG 
               
               
                 GAAGCTGTAAAGTTTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGGAAGGAATGA 
               
               
                 TTGCATCATCGATAAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGA 
               
               
                 ATGAACCTGGAAGCTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCAC 
               
               
                 AAGAAACCTCTGAAAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCT 
               
               
                 GGTGTCACTGTTGGAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCA 
               
               
                 ACTTGGAGGATCATGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAA 
               
               
                 AGGCAATACCAGGTTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTT 
               
               
                 TCTTATGGCATTTGCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCT 
               
               
                 GATCTGATTATTAATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATG 
               
               
                 TTTCCTCTGAGTTACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCT 
               
               
                 CTCTTCAGTTCCTAAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAATGACCTACATCAAA 
               
               
                 GAGCTAGGAAAAGCCATTGTCAAGAGGGAAGGAAACTCCAGCCAGAACTGGCAGCGGTTTTATCAACTGA 
               
               
                 CAAAACTCTTGGATTCTATGCATGAAGTGGTTGAAAATCTCCTTAACTATTGCTTCCAAACATTTTTGGA 
               
               
                 TAAGACCATGAGTATTGAATTCCCCGAGATGTTAGCTGAAATCATCACCAATCAGATACCAAAATATTCA 
               
               
                 AATGGAAATATCAAAAAACTTCTGTTTCATCAAAAGTGACTGCCTTAATAAGAATGGTTGCCTTAAAGAA 
               
               
                 AGTCGAATTAATAGCTTTTATTGTATAAACTATCAGTTTGTCCTGTAGAGGTTTTGTTGTTTTATTTTTT 
               
               
                 ATTGTTTTCATCTGTTGTTTTGTTTTAAATACGCACTACATGTGGTTTATAGAGGGCCAAGACTTGGCAA 
               
               
                 CAGAAGCAGTTGAGTCGTCATCACTTTTCAGTGATGGGAGAGTAGATGGTGAAATTTATTAGTTAATATA 
               
               
                 TCCCAGAAATTAGAAACCTTAATATGTGGACGTAATCTCCACAGTCAAAGAAGGATGGCACCTAAACCAC 
               
               
                 CAGTGCCCAAAGTCTGTGTGATGAACTTTCTCTTCATACTTTTTTTCACAGTTGGCTGGATGAAATTTTC 
               
               
                 TAGACTTTCTGTTGGTGTATCCCCCCCCTGTATAGTTAGGATAGCATTTTTGATTTATGCATGGAAACCT 
               
               
                 GAAAAAAAGTTTACAAGTGTATATCAGAAAAGGGAAGTTGTGCCTTTTATAGCTATTACTGTCTGGTTTT 
               
               
                 AACAATTTCCTTTATATTTAGTGAACTACGCTTGCTCATTTTTTCTTACATAATTTTTTATTCAAGTTAT 
               
               
                 TGTACAGCTGTTTAAGATGGGCAGCTAGTTCGTAGCTTTCCCAAATAAACTCTAAACATTAATCAATCAT 
               
               
                 CTGTGTGAAAATGGGTTGGTGCTTCTAACCTGATGGCACTTAGCTATCAGAAGACCACAAAAATTGACTC 
               
               
                 AAATCTCCAGTATTCTTGTCAAAAAAAAAAAAAAAAAAGCTCATATTTTGTATATATCTGCTTCAGTGGA 
               
               
                 GAATTATATAGGTTGTGCAAATTAACAGTCCTAACTGGTATAGAGCACCTAGTCCAGTGACCTGCTGGGT 
               
               
                 AAACTGTGGATGATGGTTGCAAAAGACTAATTTAAAAAATAACTACCAAGAGGCCCTGTCTGTACCTAAC 
               
               
                 GCCCTATTTTTGCAATGGCTATATGGCAAGAAAGCTGGTAAACTATTTGTCTTTCAGGACCTTTTGAAGT 
               
               
                 AGTTTGTATAACTTCTTAAAAGTTGTGATTCCAGATAACCAGCTGTAACACAGCTGAGAGACTTTTAATC 
               
               
                 AGACAAAGTAATTCCTCTCACTAAACTTTACCCAAAAACTAAATCTCTAATATGGCAAAAATGGCTAGAC 
               
               
                 ACCCATTTTCACATTCCCATCTGTCACCAATTGGTTAATCTTTCCTGATGGTACAGGAAAGCTCAGCTAC 
               
               
                 TGATTTTTGTGATTTAGAACTGTATGTCAGACATCCATGTTTGTAAAACTACACATCCCTAATGTGTGCC 
               
               
                 ATAGAGTTTAACACAAGTCCTGTGAATTTCTTCACTGTTGAAAATTATTTTAAACAAAATAGAAGCTGTA 
               
               
                 GTAGCCCTTTCTGTGTGCACCTTACCAACTTTCTGTAAACTCAAAACTTAACATATTTACTAAGCCACAA 
               
               
                 GAAATTTGATTTCTATTCAAGGTGGCCAAATTATTTGTGTAATAGAAAACTGAAAATCTAATATTAAAAA 
               
               
                 TATGGAACTTCTAATATATTTTTATATTTAGTTATAGTTTCAGATATATATCATATTGGTATTCACTAAT 
               
               
                 CTGGGAAGGGAAGGGCTACTGCAGCTTTACATGCAATTTATTAAAATGATTGTAAAATAGCTTGTATAGT 
               
               
                 GTAAAATAAGAATGATTTTTAGATGAGATTGTTTTATCATGACATGTTATATATTTTTTGTAGGGGTCAA 
               
               
                 AGAAATGCTGATGGATAACCTATATGATTTATAGTTTGTACATGCATTCATACAGGCAGCGATGGTCTCA 
               
               
                 GAAACCAAACAGTTTGCTCTAGGGGAAGAGGGAGATGGAGACTGGTCCTGTGTGCAGTGAAGGTTGCTGA 
               
               
                 GGCTCTGACCCAGTGAGATTACAGAGGAAGTTATCCTCTGCCTCCCATTCTGACCACCCTTCTCATTCCA 
               
               
                 ACAGTGAGTCTGTCAGCGCAGGTTTAGTTTACTCAATCTCCCCTTGCACTAAAGTATGTAAAGTATGTAA 
               
               
                 ACAGGAGACAGGAAGGTGGTGCTTACATCCTTAAAGGCACCATCTAATAGCGGGTTACTTTCACATACAG 
               
               
                 CCCTCCCCCAGCAGTTGAATGACAACAGAAGCTTCAGAAGTTTGGCAATAGTTTGCATAGAGGTACCAGC 
               
               
                 AATATGTAAATAGTGCAGAATCTCATAGGTTGCCAATAATACACTAATTCCTTTCTATCCTACAACAAGA 
               
               
                 GTTTATTTCCAAATAAAATGAGGACATGTTTTTGTTTTCTTTGAATGCTTTTTGAATGTTATTTGTTATT 
               
               
                 TTCAGTATTTTGGAGAAATTATTTAATAAAAAAACAATCATTTGCTTTTTGAATGCTCTCTAAAAGGGAA 
               
               
                 TGTAATATTTTAAGATGGTGTGTAACCCGGCTGGATAAATTTTTGGTGCCTAAGAAAACTGCTTGAATAT 
               
               
                 TCTTATCAATGACAGTGTTAAGTTTCAAAAAGAGCTTCTAAAACGTAGATTATCATTCCTTTATAGAATG 
               
               
                 TTATGTGGTTAAAACCAGAAAGCACATCTCACACATTAATCTGATTTTCATCCCAACAATCTTGGCGCTC 
               
               
                 AAAAAATAGAACTCAATGAGAAAAAGAAGATTATGTGCACTTCGTTGTCAATAATAAGTCAACTGATGCT 
               
               
                 CATCGACAACTATAGGAGGCTTTTCATTAAATGGGAAAAGAAGCTGTGCCCTTTTAGGATACGTGGGGGA 
               
               
                 AAAGAAAGTCATCTTAATTATGTTTAATTGTGGATTTAAGTGCTATATGGTGGTGCTGTTTGAAAGCAGA 
               
               
                 TTTATTTCCTATGTATGTGTTATCTGGCCATCCCAACCCAAACTGTTGAAGTTTGTAGTAACTTCAGTGA 
               
               
                 GAGTTGGTTACTCACAACAAATCCTGAAAAGTATTTTTAGTGTTTGTAGGTATTCTGTGGGATACTATAC 
               
               
                 AAGCAGAACTGAGGCACTTAGGACATAACACTTTTGGGGTATATATATCCAAATGCCTAAAACTATGGGA 
               
               
                 GGAAACCTTGGCCACCCCAAAAGGAAAACTAACATGATTTGTGTCTATGAAGTGCTGGATAATTAGCATG 
               
               
                 GGATGAGCTCTGGGCATGCCATGAAGGAAAGCCACGCTCCCTTCAGAATTCAGAGGCAGGGAGCAATTCC 
               
               
                 AGTTTCACCTAAGTCTCATAATTTTAGTTCCCTTTTAAAAACCCTGAAAACTACATCACCATGGAATGAA 
               
               
                 AAATATTGTTATACAATACATTGATCTGTCAAACTTCCAGAACCATGGTAGCCTTCAGTGAGATTTCCAT 
               
               
                 CTTGGCTGGTCACTCCCTGACTGTAGCTGTAGGTGAATGTGTTTTTGTGTGTGTGTGTCTGGTTTTAGTG 
               
               
                 TCAGAAGGGAAATAAAAGTGTAAGGAGGACACTTTAAACCCTTTGGGTGGAGTTTCGTAATTTCCCAGAC 
               
               
                 TATTTTCAAGCAACCTGGTCCACCCAGGATTAGTGACCAGGTTTTCAGGAAAGGATTTGCTTCTCTCTAG 
               
               
                 AAAATGTCTGAAAGGATTTTATTTTCTGATGAAAGGCTGTATGAAAATACCCTCCTCAAATAACTTGCTT 
               
               
                 AACTACATATAGATTCAAGTGTGTCAATATTCTATTTTGTATATTAAATGCTATATAATGGGGACAAATC 
               
               
                 TATATTATACTGTGTATGGCATTATTAAGAAGCTTTTTCATTATTTTTTATCACAGTAATTTTAAAATGT 
               
               
                 GTAAAAATTAAAACCAGTGACTCCTGTTTAAAAATAAAAGTTGTAGTTTTTTATTCATGCTGAATAATAA 
               
               
                 TCTGTAGTTAAAAAAAAAGTGTCTTTTTACCTACGCAGTGAAATGTCAGACTGTAAAACCTTGTGTGGAA 
               
               
                 ATGTTTAACTTTTATTTTTTCATTTAAATTTGCTGTTCTGGTATTACCAAACCACACATTTGTACCGAAT 
               
               
                 TGGCAGTAAATGTTAGCCATTTACAGCAATGCCAAATATGGAGAAACATCATAATAAAAAAATCTGCTTT 
               
               
                 TTCATTA 
               
               
                   
               
               
                 SEQ ID NO: 17 Human GR Transcript Variant 4 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001018076.1) 
               
               
                 CTTCTCTCCCAGTGCGAGAGCGCGGCGGCGGCAGCTGAAGACCCGGCCGCCCAGATGATGCGGTGGTGGG 
               
               
                 GGACCTGCCGGCACGCGACTCCCCCCGGGCCCAAATTGATATTCACTGATGGACTCCAAAGAATCATTAA 
               
               
                 CTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAGGGGAGATGTGATGGACTTCTATAA 
               
               
                 AACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCCTCACTGGCTGTCGCTTCTCAATCA 
               
               
                 GACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAGTAAGCAATGCGCAGCAGCCAGATC 
               
               
                 TGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGACAGAAACAAAAGTGATGGGAAATGA 
               
               
                 CCTGGGATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAAACAGACTTAAAGCTTTTGGAAGAA 
               
               
                 AGCATTGCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCAAGAGTTCAGCATCCACTGCTGTGT 
               
               
                 CTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGTATCTTCAGAACAGCAACATTTGAA 
               
               
                 GGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACAGACCAAAGCACCTTTGACATTTTG 
               
               
                 CAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATGAGAGTCCTTGGAGATCAGACCTGT 
               
               
                 TGATAGATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGATTCATTCCTTTTGGAAGGAAACTC 
               
               
                 GAATGAGGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAAATTAAGGATAATGGAGATCTGGTT 
               
               
                 TTGTCAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAAAAGAAGATTTCATCGAACTCTGCA 
               
               
                 CCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCAGGCAAGCTTTCCTGGAGCAAATAT 
               
               
                 AATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACCTCTGGAGGACAGATGTACCACTAT 
               
               
                 GACATGAATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTATTTTTAATGTCATTCCACCAATTC 
               
               
                 CCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGACAACTTGACTTCTCTGGGGACTCT 
               
               
                 GAACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCCAGCATGAGACCAGATGTAAGCTCT 
               
               
                 CCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAACTCTGCCTGGTGTGCTCTGATGAAG 
               
               
                 CTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGTTTTCTTCAAAAGAGCAGTGGAAGG 
               
               
                 ACAGCACAATTACCTATGTGCTGGAAGGAATGATTGCATCATCGATAAAATTCGAAGAAAAAACTGCCCA 
               
               
                 GCATGCCGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGGAAGCTCGAAAAACAAAGAAAAAAATAA 
               
               
                 AAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGAAAATCCTGGTAACAAAACAATAGT 
               
               
                 TCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTGGAGGTTATTGAACCTGAAGTGTTA 
               
               
                 TATGCAGGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGATCATGACTACGCTCAACATGTTAGGAG 
               
               
                 GGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACCAGGTTTCAGGAACTTACACCTGGATGA 
               
               
                 CCAAATGACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCATTTGCTCTGGGGTGGAGATCATATAGA 
               
               
                 CAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTAATGAGCAGAGAATGACTCTACCCT 
               
               
                 GCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAGTTACACAGGCTTCAGGTATCTTATGA 
               
               
                 AGAGTATCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGTTCCTAAGGACGGTCTGAAGAGCCAAGAG 
               
               
                 CTATTTGATGAAATTAGAATGACCTACATCAAAGAGCTAGGAAAAGCCATTGTCAAGAGGGAAGGAAACT 
               
               
                 CCAGCCAGAACTGGCAGCGGTTTTATCAACTGACAAAACTCTTGGATTCTATGCATGAAGTGGTTGAAAA 
               
               
                 TCTCCTTAACTATTGCTTCCAAACATTTTTGGATAAGACCATGAGTATTGAATTCCCCGAGATGTTAGCT 
               
               
                 GAAATCATCACCAATCAGATACCAAAATATTCAAATGGAAATATCAAAAAACTTCTGTTTCATCAAAAGT 
               
               
                 GACTGCCTTAATAAGAATGGTTGCCTTAAAGAAAGTCGAATTAATAGCTTTTATTGTATAAACTATCAGT 
               
               
                 TTGTCCTGTAGAGGTTTTGTTGTTTTATTTTTTATTGTTTTCATCTGTTGTTTTGTTTTAAATACGCACT 
               
               
                 ACATGTGGTTTATAGAGGGCCAAGACTTGGCAACAGAAGCAGTTGAGTCGTCATCACTTTTCAGTGATGG 
               
               
                 GAGAGTAGATGGTGAAATTTATTAGTTAATATATCCCAGAAATTAGAAACCTTAATATGTGGACGTAATC 
               
               
                 TCCACAGTCAAAGAAGGATGGCACCTAAACCACCAGTGCCCAAAGTCTGTGTGATGAACTTTCTCTTCAT 
               
               
                 ACTTTTTTTCACAGTTGGCTGGATGAAATTTTCTAGACTTTCTGTTGGTGTATCCCCCCCCTGTATAGTT 
               
               
                 AGGATAGCATTTTTGATTTATGCATGGAAACCTGAAAAAAAGTTTACAAGTGTATATCAGAAAAGGGAAG 
               
               
                 TTGTGCCTTTTATAGCTATTACTGTCTGGTTTTAACAATTTCCTTTATATTTAGTGAACTACGCTTGCTC 
               
               
                 ATTTTTTCTTACATAATTTTTTATTCAAGTTATTGTACAGCTGTTTAAGATGGGCAGCTAGTTCGTAGCT 
               
               
                 TTCCCAAATAAACTCTAAACATTAATCAATCATCTGTGTGAAAATGGGTTGGTGCTTCTAACCTGATGGC 
               
               
                 ACTTAGCTATCAGAAGACCACAAAAATTGACTCAAATCTCCAGTATTCTTGTCAAAAAAAAAAAAAAAAA 
               
               
                 AGCTCATATTTTGTATATATCTGCTTCAGTGGAGAATTATATAGGTTGTGCAAATTAACAGTCCTAACTG 
               
               
                 GTATAGAGCACCTAGTCCAGTGACCTGCTGGGTAAACTGTGGATGATGGTTGCAAAAGACTAATTTAAAA 
               
               
                 AATAACTACCAAGAGGCCCTGTCTGTACCTAACGCCCTATTTTTGCAATGGCTATATGGCAAGAAAGCTG 
               
               
                 GTAAACTATTTGTCTTTCAGGACCTTTTGAAGTAGTTTGTATAACTTCTTAAAAGTTGTGATTCCAGATA 
               
               
                 ACCAGCTGTAACACAGCTGAGAGACTTTTAATCAGACAAAGTAATTCCTCTCACTAAACTTTACCCAAAA 
               
               
                 ACTAAATCTCTAATATGGCAAAAATGGCTAGACACCCATTTTCACATTCCCATCTGTCACCAATTGGTTA 
               
               
                 ATCTTTCCTGATGGTACAGGAAAGCTCAGCTACTGATTTTTGTGATTTAGAACTGTATGTCAGACATCCA 
               
               
                 TGTTTGTAAAACTACACATCCCTAATGTGTGCCATAGAGTTTAACACAAGTCCTGTGAATTTCTTCACTG 
               
               
                 TTGAAAATTATTTTAAACAAAATAGAAGCTGTAGTAGCCCTTTCTGTGTGCACCTTACCAACTTTCTGTA 
               
               
                 AACTCAAAACTTAACATATTTACTAAGCCACAAGAAATTTGATTTCTATTCAAGGTGGCCAAATTATTTG 
               
               
                 TGTAATAGAAAACTGAAAATCTAATATTAAAAATATGGAACTTCTAATATATTTTTATATTTAGTTATAG 
               
               
                 TTTCAGATATATATCATATTGGTATTCACTAATCTGGGAAGGGAAGGGCTACTGCAGCTTTACATGCAAT 
               
               
                 TTATTAAAATGATTGTAAAATAGCTTGTATAGTGTAAAATAAGAATGATTTTTAGATGAGATTGTTTTAT 
               
               
                 CATGACATGTTATATATTTTTTGTAGGGGTCAAAGAAATGCTGATGGATAACCTATATGATTTATAGTTT 
               
               
                 GTACATGCATTCATACAGGCAGCGATGGTCTCAGAAACCAAACAGTTTGCTCTAGGGGAAGAGGGAGATG 
               
               
                 GAGACTGGTCCTGTGTGCAGTGAAGGTTGCTGAGGCTCTGACCCAGTGAGATTACAGAGGAAGTTATCCT 
               
               
                 CTGCCTCCCATTCTGACCACCCTTCTCATTCCAACAGTGAGTCTGTCAGCGCAGGTTTAGTTTACTCAAT 
               
               
                 CTCCCCTTGCACTAAAGTATGTAAAGTATGTAAACAGGAGACAGGAAGGTGGTGCTTACATCCTTAAAGG 
               
               
                 CACCATCTAATAGCGGGTTACTTTCACATACAGCCCTCCCCCAGCAGTTGAATGACAACAGAAGCTTCAG 
               
               
                 AAGTTTGGCAATAGTTTGCATAGAGGTACCAGCAATATGTAAATAGTGCAGAATCTCATAGGTTGCCAAT 
               
               
                 AATACACTAATTCCTTTCTATCCTACAACAAGAGTTTATTTCCAAATAAAATGAGGACATGTTTTTGTTT 
               
               
                 TCTTTGAATGCTTTTTGAATGTTATTTGTTATTTTCAGTATTTTGGAGAAATTATTTAATAAAAAAACAA 
               
               
                 TCATTTGCTTTTTGAATGCTCTCTAAAAGGGAATGTAATATTTTAAGATGGTGTGTAACCCGGCTGGATA 
               
               
                 AATTTTTGGTGCCTAAGAAAACTGCTTGAATATTCTTATCAATGACAGTGTTAAGTTTCAAAAAGAGCTT 
               
               
                 CTAAAACGTAGATTATCATTCCTTTATAGAATGTTATGTGGTTAAAACCAGAAAGCACATCTCACACATT 
               
               
                 AATCTGATTTTCATCCCAACAATCTTGGCGCTCAAAAAATAGAACTCAATGAGAAAAAGAAGATTATGTG 
               
               
                 CACTTCGTTGTCAATAATAAGTCAACTGATGCTCATCGACAACTATAGGAGGCTTTTCATTAAATGGGAA 
               
               
                 AAGAAGCTGTGCCCTTTTAGGATACGTGGGGGAAAAGAAAGTCATCTTAATTATGTTTAATTGTGGATTT 
               
               
                 AAGTGCTATATGGTGGTGCTGTTTGAAAGCAGATTTATTTCCTATGTATGTGTTATCTGGCCATCCCAAC 
               
               
                 CCAAACTGTTGAAGTTTGTAGTAACTTCAGTGAGAGTTGGTTACTCACAACAAATCCTGAAAAGTATTTT 
               
               
                 TAGTGTTTGTAGGTATTCTGTGGGATACTATACAAGCAGAACTGAGGCACTTAGGACATAACACTTTTGG 
               
               
                 GGTATATATATCCAAATGCCTAAAACTATGGGAGGAAACCTTGGCCACCCCAAAAGGAAAACTAACATGA 
               
               
                 TTTGTGTCTATGAAGTGCTGGATAATTAGCATGGGATGAGCTCTGGGCATGCCATGAAGGAAAGCCACGC 
               
               
                 TCCCTTCAGAATTCAGAGGCAGGGAGCAATTCCAGTTTCACCTAAGTCTCATAATTTTAGTTCCCTTTTA 
               
               
                 AAAACCCTGAAAACTACATCACCATGGAATGAAAAATATTGTTATACAATACATTGATCTGTCAAACTTC 
               
               
                 CAGAACCATGGTAGCCTTCAGTGAGATTTCCATCTTGGCTGGTCACTCCCTGACTGTAGCTGTAGGTGAA 
               
               
                 TGTGTTTTTGTGTGTGTGTGTCTGGTTTTAGTGTCAGAAGGGAAATAAAAGTGTAAGGAGGACACTTTAA 
               
               
                 ACCCTTTGGGTGGAGTTTCGTAATTTCCCAGACTATTTTCAAGCAACCTGGTCCACCCAGGATTAGTGAC 
               
               
                 CAGGTTTTCAGGAAAGGATTTGCTTCTCTCTAGAAAATGTCTGAAAGGATTTTATTTTCTGATGAAAGGC 
               
               
                 TGTATGAAAATACCCTCCTCAAATAACTTGCTTAACTACATATAGATTCAAGTGTGTCAATATTCTATTT 
               
               
                 TGTATATTAAATGCTATATAATGGGGACAAATCTATATTATACTGTGTATGGCATTATTAAGAAGCTTTT 
               
               
                 TCATTATTTTTTATCACAGTAATTTTAAAATGTGTAAAAATTAAAACCAGTGACTCCTGTTTAAAAATAA 
               
               
                 AAGTTGTAGTTTTTTATTCATGCTGAATAATAATCTGTAGTTAAAAAAAAAGTGTCTTTTTACCTACGCA 
               
               
                 GTGAAATGTCAGACTGTAAAACCTTGTGTGGAAATGTTTAACTTTTATTTTTTCATTTAAATTTGCTGTT 
               
               
                 CTGGTATTACCAAACCACACATTTGTACCGAATTGGCAGTAAATGTTAGCCATTTACAGCAATGCCAAAT 
               
               
                 ATGGAGAAACATCATAATAAAAAAATCTGCTTTTTCATTA 
               
               
                   
               
               
                 SEQ ID NO: 18 Human GR Transcript Variant 5 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001018077.1) 
               
               
                 AGGTTATGTAAGGGTTTGCTTTCACCCCATTCAAAAGGTACCTCTTCCTCTTCTCTTGCTCCCTCTCGCC 
               
               
                 CTCATTCTTGTGCCTATGCAGACATTTGAGTAGAGGCGAATCACTTTCACTTCTGCTGGGGAAATTGCAA 
               
               
                 CACGCTTCTTTAAATGGCAGAGAGAAGGAGAAAACTTAGATCTTCTGATACCAAATCACTGGACCTTAGA 
               
               
                 AGGTCAGAAATCTTTCAAGCCCTGCAGGACCGTAAAATGCGCATGTGTCCAACGGAAGCACTGGGGCATG 
               
               
                 AGTGGGGAAGGAATAGAAACAGAAAGAGGGTAAGAGAAGAAAAAAGGGAAAGTGGTGAAGGCAGGGAGGA 
               
               
                 AAATTGCTTAGTGTGAATATGCACGCATTCATTTAGTTTTCAAATCCTTGTTGAGCATGATAAAATTCCC 
               
               
                 AGCATCAGACCTCACATGTTGGTTTCCATTAGGATCTGCCTGGGGGAATATCTGCTGAATCAGTGGCTCT 
               
               
                 GAGCTGAACTAGGAAATTCACCATAATTAGGAGAGTCACTGTATTTCTCTCCAAAAAAAAAAAAGTTATA 
               
               
                 CCCGAGAGACAGGATCTTCTGATCTGAAATTTTCTTCACTTCTGAAATTCTCTGGTTTGTGCTCATCGTT 
               
               
                 GGTAGCTATTTGTTCATCAAGAGTTGTGTAGCTGGCTTCTTCTGAAAAAAGGAATCTGCGTCATATCTAA 
               
               
                 GTCAGATTTCATTCTGGTGCTCTCAGAGCAGTTAGCCCAGGAAAGGGGCCAGCTTCTGTGACGACTGCTG 
               
               
                 CAGAGGCAGGTGCAGTTTGTGTGCCACAGATATTAACTTTGATAAGCACTTAATGAGTGCCTTCTCTGTG 
               
               
                 CGAGAATGGGGAGGAACAAAATGCAGCTCCTACCCTCCTCGGGCTTTAGTTGTACCTTAATAACAGGAAT 
               
               
                 TTTCATCTGCCTGGCTCCTTTCCTCAAAGAACAAAGAAGACTTTGCTTCATTAAAGTGTCTGAGAAGGAA 
               
               
                 GTTGATATTCACTGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCT 
               
               
                 TGCTCAGGAGAGGGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCT 
               
               
                 GCGTCTTCACCCTCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTC 
               
               
                 CAAAAGGCTCAGTAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTA 
               
               
                 TATGGGAGAGACAGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCTT 
               
               
                 TCCTCGGGGGAAACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTTC 
               
               
                 CAGAGAACCCCAAGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAAC 
               
               
                 TCACTCTGATGTATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAA 
               
               
                 TTGTATACCACAGACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTA 
               
               
                 AAGAGACGAATGAGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGGC 
               
               
                 GGGAGAAGACGATTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGAC 
               
               
                 ACTAAACCCAAAATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAAG 
               
               
                 TGAAAACAGAAAAAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCAC 
               
               
                 AGTTTACTGTCAGGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCAT 
               
               
                 GGTGTGAGTACCTCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAGG 
               
               
                 ATCAGAAGCCTATTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGG 
               
               
                 ATCTGGAGATGACAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGGC 
               
               
                 TATTCAAGCCCCAGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGAC 
               
               
                 CACCTCCCAAACTCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGG 
               
               
                 AAGCTGTAAAGTTTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGGAAGGAATGAT 
               
               
                 TGCATCATCGATAAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGAA 
               
               
                 TGAACCTGGAAGCTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCACA 
               
               
                 AGAAACCTCTGAAAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTG 
               
               
                 GTGTCACTGTTGGAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAA 
               
               
                 CTTGGAGGATCATGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAA 
               
               
                 GGCAATACCAGGTTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTTT 
               
               
                 CTTATGGCATTTGCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTG 
               
               
                 ATCTGATTATTAATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGT 
               
               
                 TTCCTCTGAGTTACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCTC 
               
               
                 TCTTCAGTTCCTAAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAATGACCTACATCAAAG 
               
               
                 AGCTAGGAAAAGCCATTGTCAAGAGGGAAGGAAACTCCAGCCAGAACTGGCAGCGGTTTTATCAACTGAC 
               
               
                 AAAACTCTTGGATTCTATGCATGAAGTGGTTGAAAATCTCCTTAACTATTGCTTCCAAACATTTTTGGAT 
               
               
                 AAGACCATGAGTATTGAATTCCCCGAGATGTTAGCTGAAATCATCACCAATCAGATACCAAAATATTCAA 
               
               
                 ATGGAAATATCAAAAAACTTCTGTTTCATCAAAAGTGACTGCCTTAATAAGAATGGTTGCCTTAAAGAAA 
               
               
                 GTCGAATTAATAGCTTTTATTGTATAAACTATCAGTTTGTCCTGTAGAGGTTTTGTTGTTTTATTTTTTA 
               
               
                 TTGTTTTCATCTGTTGTTTTGTTTTAAATACGCACTACATGTGGTTTATAGAGGGCCAAGACTTGGCAAC 
               
               
                 AGAAGCAGTTGAGTCGTCATCACTTTTCAGTGATGGGAGAGTAGATGGTGAAATTTATTAGTTAATATAT 
               
               
                 CCCAGAAATTAGAAACCTTAATATGTGGACGTAATCTCCACAGTCAAAGAAGGATGGCACCTAAACCACC 
               
               
                 AGTGCCCAAAGTCTGTGTGATGAACTTTCTCTTCATACTTTTTTTCACAGTTGGCTGGATGAAATTTTCT 
               
               
                 AGACTTTCTGTTGGTGTATCCCCCCCCTGTATAGTTAGGATAGCATTTTTGATTTATGCATGGAAACCTG 
               
               
                 AAAAAAAGTTTACAAGTGTATATCAGAAAAGGGAAGTTGTGCCTTTTATAGCTATTACTGTCTGGTTTTA 
               
               
                 ACAATTTCCTTTATATTTAGTGAACTACGCTTGCTCATTTTTTCTTACATAATTTTTTATTCAAGTTATT 
               
               
                 GTACAGCTGTTTAAGATGGGCAGCTAGTTCGTAGCTTTCCCAAATAAACTCTAAACATTAATCAATCATC 
               
               
                 TGTGTGAAAATGGGTTGGTGCTTCTAACCTGATGGCACTTAGCTATCAGAAGACCACAAAAATTGACTCA 
               
               
                 AATCTCCAGTATTCTTGTCAAAAAAAAAAAAAAAAAAGCTCATATTTTGTATATATCTGCTTCAGTGGAG 
               
               
                 AATTATATAGGTTGTGCAAATTAACAGTCCTAACTGGTATAGAGCACCTAGTCCAGTGACCTGCTGGGTA 
               
               
                 AACTGTGGATGATGGTTGCAAAAGACTAATTTAAAAAATAACTACCAAGAGGCCCTGTCTGTACCTAACG 
               
               
                 CCCTATTTTTGCAATGGCTATATGGCAAGAAAGCTGGTAAACTATTTGTCTTTCAGGACCTTTTGAAGTA 
               
               
                 GTTTGTATAACTTCTTAAAAGTTGTGATTCCAGATAACCAGCTGTAACACAGCTGAGAGACTTTTAATCA 
               
               
                 GACAAAGTAATTCCTCTCACTAAACTTTACCCAAAAACTAAATCTCTAATATGGCAAAAATGGCTAGACA 
               
               
                 CCCATTTTCACATTCCCATCTGTCACCAATTGGTTAATCTTTCCTGATGGTACAGGAAAGCTCAGCTACT 
               
               
                 GATTTTTGTGATTTAGAACTGTATGTCAGACATCCATGTTTGTAAAACTACACATCCCTAATGTGTGCCA 
               
               
                 TAGAGTTTAACACAAGTCCTGTGAATTTCTTCACTGTTGAAAATTATTTTAAACAAAATAGAAGCTGTAG 
               
               
                 TAGCCCTTTCTGTGTGCACCTTACCAACTTTCTGTAAACTCAAAACTTAACATATTTACTAAGCCACAAG 
               
               
                 AAATTTGATTTCTATTCAAGGTGGCCAAATTATTTGTGTAATAGAAAACTGAAAATCTAATATTAAAAAT 
               
               
                 ATGGAACTTCTAATATATTTTTATATTTAGTTATAGTTTCAGATATATATCATATTGGTATTCACTAATC 
               
               
                 TGGGAAGGGAAGGGCTACTGCAGCTTTACATGCAATTTATTAAAATGATTGTAAAATAGCTTGTATAGTG 
               
               
                 TAAAATAAGAATGATTTTTAGATGAGATTGTTTTATCATGACATGTTATATATTTTTTGTAGGGGTCAAA 
               
               
                 GAAATGCTGATGGATAACCTATATGATTTATAGTTTGTACATGCATTCATACAGGCAGCGATGGTCTCAG 
               
               
                 AAACCAAACAGTTTGCTCTAGGGGAAGAGGGAGATGGAGACTGGTCCTGTGTGCAGTGAAGGTTGCTGAG 
               
               
                 GCTCTGACCCAGTGAGATTACAGAGGAAGTTATCCTCTGCCTCCCATTCTGACCACCCTTCTCATTCCAA 
               
               
                 CAGTGAGTCTGTCAGCGCAGGTTTAGTTTACTCAATCTCCCCTTGCACTAAAGTATGTAAAGTATGTAAA 
               
               
                 CAGGAGACAGGAAGGTGGTGCTTACATCCTTAAAGGCACCATCTAATAGCGGGTTACTTTCACATACAGC 
               
               
                 CCTCCCCCAGCAGTTGAATGACAACAGAAGCTTCAGAAGTTTGGCAATAGTTTGCATAGAGGTACCAGCA 
               
               
                 ATATGTAAATAGTGCAGAATCTCATAGGTTGCCAATAATACACTAATTCCTTTCTATCCTACAACAAGAG 
               
               
                 TTTATTTCCAAATAAAATGAGGACATGTTTTTGTTTTCTTTGAATGCTTTTTGAATGTTATTTGTTATTT 
               
               
                 TCAGTATTTTGGAGAAATTATTTAATAAAAAAACAATCATTTGCTTTTTGAATGCTCTCTAAAAGGGAAT 
               
               
                 GTAATATTTTAAGATGGTGTGTAACCCGGCTGGATAAATTTTTGGTGCCTAAGAAAACTGCTTGAATATT 
               
               
                 CTTATCAATGACAGTGTTAAGTTTCAAAAAGAGCTTCTAAAACGTAGATTATCATTCCTTTATAGAATGT 
               
               
                 TATGTGGTTAAAACCAGAAAGCACATCTCACACATTAATCTGATTTTCATCCCAACAATCTTGGCGCTCA 
               
               
                 AAAAATAGAACTCAATGAGAAAAAGAAGATTATGTGCACTTCGTTGTCAATAATAAGTCAACTGATGCTC 
               
               
                 ATCGACAACTATAGGAGGCTTTTCATTAAATGGGAAAAGAAGCTGTGCCCTTTTAGGATACGTGGGGGAA 
               
               
                 AAGAAAGTCATCTTAATTATGTTTAATTGTGGATTTAAGTGCTATATGGTGGTGCTGTTTGAAAGCAGAT 
               
               
                 TTATTTCCTATGTATGTGTTATCTGGCCATCCCAACCCAAACTGTTGAAGTTTGTAGTAACTTCAGTGAG 
               
               
                 AGTTGGTTACTCACAACAAATCCTGAAAAGTATTTTTAGTGTTTGTAGGTATTCTGTGGGATACTATACA 
               
               
                 AGCAGAACTGAGGCACTTAGGACATAACACTTTTGGGGTATATATATCCAAATGCCTAAAACTATGGGAG 
               
               
                 GAAACCTTGGCCACCCCAAAAGGAAAACTAACATGATTTGTGTCTATGAAGTGCTGGATAATTAGCATGG 
               
               
                 GATGAGCTCTGGGCATGCCATGAAGGAAAGCCACGCTCCCTTCAGAATTCAGAGGCAGGGAGCAATTCCA 
               
               
                 GTTTCACCTAAGTCTCATAATTTTAGTTCCCTTTTAAAAACCCTGAAAACTACATCACCATGGAATGAAA 
               
               
                 AATATTGTTATACAATACATTGATCTGTCAAACTTCCAGAACCATGGTAGCCTTCAGTGAGATTTCCATC 
               
               
                 TTGGCTGGTCACTCCCTGACTGTAGCTGTAGGTGAATGTGTTTTTGTGTGTGTGTGTCTGGTTTTAGTGT 
               
               
                 CAGAAGGGAAATAAAAGTGTAAGGAGGACACTTTAAACCCTTTGGGTGGAGTTTCGTAATTTCCCAGACT 
               
               
                 ATTTTCAAGCAACCTGGTCCACCCAGGATTAGTGACCAGGTTTTCAGGAAAGGATTTGCTTCTCTCTAGA 
               
               
                 AAATGTCTGAAAGGATTTTATTTTCTGATGAAAGGCTGTATGAAAATACCCTCCTCAAATAACTTGCTTA 
               
               
                 ACTACATATAGATTCAAGTGTGTCAATATTCTATTTTGTATATTAAATGCTATATAATGGGGACAAATCT 
               
               
                 ATATTATACTGTGTATGGCATTATTAAGAAGCTTTTTCATTATTTTTTATCACAGTAATTTTAAAATGTG 
               
               
                 TAAAAATTAAAACCAGTGACTCCTGTTTAAAAATAAAAGTTGTAGTTTTTTATTCATGCTGAATAATAAT 
               
               
                 CTGTAGTTAAAAAAAAAGTGTCTTTTTACCTACGCAGTGAAATGTCAGACTGTAAAACCTTGTGTGGAAA 
               
               
                 TGTTTAACTTTTATTTTTTCATTTAAATTTGCTGTTCTGGTATTACCAAACCACACATTTGTACCGAATT 
               
               
                 GGCAGTAAATGTTAGCCATTTACAGCAATGCCAAATATGGAGAAACATCATAATAAAAAAATCTGCTTTT 
               
               
                 TCATTA 
               
               
                   
               
               
                 SEQ ID NO: 19 Human GR Transcript Variant 6 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001020825.1) 
               
               
                 GGCGCCGCCTCCACCCGCTCCCCGCTCGGTCCCGCTCGCTCGCCCAGGCCGGGCTGCCCTTTCGCGTGTC 
               
               
                 CGCGCTCTCTTCCCTCCGCCGCCGCCTCCTCCATTTTGCGAGCTCGTGTCTGTGACGGGAGCCCGAGTCA 
               
               
                 CCGCCTGCCCGTCGGGGACGGATTCTGTGGGTGGAAGGAGACGCCGCAGCCGGAGCGGCCGAAGCAGCTG 
               
               
                 GGACCGGGACGGGGCACGCGCGCCCGGAACCTCGACCCGCGGAGCCCGGCGCGGGGCGGAGGGCTGGCTT 
               
               
                 GTCAGCTGGGCAATGGGAGACTTTCTTAAATAGGGGCTCTCCCCCCACCCATGGAGAAAGGGGCGGCTGT 
               
               
                 TTACTTCCTTTTTTTAGAAAAAAAAAATATATTTCCCTCCTGCTCCTTCTGCGTTCACAAGCTAAGTTGT 
               
               
                 TTATCTCGGCTGCGGCGGGAACTGCGGACGGTGGCGGGCGAGCGGCTCCTCTGCCAGAGTTGATATTCAC 
               
               
                 TGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAG 
               
               
                 GGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCC 
               
               
                 TCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAG 
               
               
                 TAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGAC 
               
               
                 AGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAA 
               
               
                 ACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCA 
               
               
                 AGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGT 
               
               
                 ATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACA 
               
               
                 GACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATG 
               
               
                 AGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGA 
               
               
                 TTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAA 
               
               
                 ATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAA 
               
               
                 AAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCA 
               
               
                 GGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACC 
               
               
                 TCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTA 
               
               
                 TTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGA 
               
               
                 CAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCC 
               
               
                 AGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAAC 
               
               
                 TCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGT 
               
               
                 TTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGGAAGGAATGATTGCATCATCGAT 
               
               
                 AAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGGAAG 
               
               
                 CTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGA 
               
               
                 AAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTG 
               
               
                 GAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGATCA 
               
               
                 TGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACCAGG 
               
               
                 TTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCATTT 
               
               
                 GCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTA 
               
               
                 ATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAGTT 
               
               
                 ACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGTTCCT 
               
               
                 AAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAATGACCTACATCAAAGAGCTAGGAAAAG 
               
               
                 CCATTGTCAAGAGGGAAGGAAACTCCAGCCAGAACTGGCAGCGGTTTTATCAACTGACAAAACTCTTGGA 
               
               
                 TTCTATGCATGAAAATGTTATGTGGTTAAAACCAGAAAGCACATCTCACACATTAATCTGATTTTCATCC 
               
               
                 CAACAATCTTGGCGCTCAAAAAATAGAACTCAATGAGAAAAAGAAGATTATGTGCACTTCGTTGTCAATA 
               
               
                 ATAAGTCAACTGATGCTCATCGACAACTATAGGAGGCTTTTCATTAAATGGGAAAAGAAGCTGTGCCCTT 
               
               
                 TTAGGATACGTGGGGGAAAAGAAAGTCATCTTAATTATGTTTAATTGTGGATTTAAGTGCTATATGGTGG 
               
               
                 TGCTGTTTGAAAGCAGATTTATTTCCTATGTATGTGTTATCTGGCCATCCCAACCCAAACTGTTGAAGTT 
               
               
                 TGTAGTAACTTCAGTGAGAGTTGGTTACTCACAACAAATCCTGAAAAGTATTTTTAGTGTTTGTAGGTAT 
               
               
                 TCTGTGGGATACTATACAAGCAGAACTGAGGCACTTAGGACATAACACTTTTGGGGTATATATATCCAAA 
               
               
                 TGCCTAAAACTATGGGAGGAAACCTTGGCCACCCCAAAAGGAAAACTAACATGATTTGTGTCTATGAAGT 
               
               
                 GCTGGATAATTAGCATGGGATGAGCTCTGGGCATGCCATGAAGGAAAGCCACGCTCCCTTCAGAATTCAG 
               
               
                 AGGCAGGGAGCAATTCCAGTTTCACCTAAGTCTCATAATTTTAGTTCCCTTTTAAAAACCCTGAAAACTA 
               
               
                 CATCACCATGGAATGAAAAATATTGTTATACAATACATTGATCTGTCAAACTTCCAGAACCATGGTAGCC 
               
               
                 TTCAGTGAGATTTCCATCTTGGCTGGTCACTCCCTGACTGTAGCTGTAGGTGAATGTGTTTTTGTGTGTG 
               
               
                 TGTGTCTGGTTTTAGTGTCAGAAGGGAAATAAAAGTGTAAGGAGGACACTTTAAACCCTTTGGGTGGAGT 
               
               
                 TTCGTAATTTCCCAGACTATTTTCAAGCAACCTGGTCCACCCAGGATTAGTGACCAGGTTTTCAGGAAAG 
               
               
                 GATTTGCTTCTCTCTAGAAAATGTCTGAAAGGATTTTATTTTCTGATGAAAGGCTGTATGAAAATACCCT 
               
               
                 CCTCAAATAACTTGCTTAACTACATATAGATTCAAGTGTGTCAATATTCTATTTTGTATATTAAATGCTA 
               
               
                 TATAATGGGGACAAATCTATATTATACTGTGTATGGCATTATTAAGAAGCTTTTTCATTATTTTTTATCA 
               
               
                 CAGTAATTTTAAAATGTGTAAAAATTAAAACCAGTGACTCCTGTTTAAAAATAAAAGTTGTAGTTTTTTA 
               
               
                 TTCATGCTGAATAATAATCTGTAGTTAAAAAAAAAGTGTCTTTTTACCTACGCAGTGAAATGTCAGACTG 
               
               
                 TAAAACCTTGTGTGGAAATGTTTAACTTTTATTTTTTCATTTAAATTTGCTGTTCTGGTATTACCAAACC 
               
               
                 ACACATTTGTACCGAATTGGCAGTAAATGTTAGCCATTTACAGCAATGCCAAATATGGAGAAACATCATA 
               
               
                 ATAAAAAAATCTGCTTTTTCATTA 
               
               
                   
               
               
                 SEQ ID NO: 20 Human GR Transcript Variant 7 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001024094.1) 
               
               
                 GGCGCCGCCTCCACCCGCTCCCCGCTCGGTCCCGCTCGCTCGCCCAGGCCGGGCTGCCCTTTCGCGTGTC 
               
               
                 CGCGCTCTCTTCCCTCCGCCGCCGCCTCCTCCATTTTGCGAGCTCGTGTCTGTGACGGGAGCCCGAGTCA 
               
               
                 CCGCCTGCCCGTCGGGGACGGATTCTGTGGGTGGAAGGAGACGCCGCAGCCGGAGCGGCCGAAGCAGCTG 
               
               
                 GGACCGGGACGGGGCACGCGCGCCCGGAACCTCGACCCGCGGAGCCCGGCGCGGGGCGGAGGGCTGGCTT 
               
               
                 GTCAGCTGGGCAATGGGAGACTTTCTTAAATAGGGGCTCTCCCCCCACCCATGGAGAAAGGGGCGGCTGT 
               
               
                 TTACTTCCTTTTTTTAGAAAAAAAAAATATATTTCCCTCCTGCTCCTTCTGCGTTCACAAGCTAAGTTGT 
               
               
                 TTATCTCGGCTGCGGCGGGAACTGCGGACGGTGGCGGGCGAGCGGCTCCTCTGCCAGAGTTGATATTCAC 
               
               
                 TGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAG 
               
               
                 GGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCC 
               
               
                 TCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAG 
               
               
                 TAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGAC 
               
               
                 AGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAA 
               
               
                 ACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCA 
               
               
                 AGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGT 
               
               
                 ATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACA 
               
               
                 GACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATG 
               
               
                 AGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGA 
               
               
                 TTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAA 
               
               
                 ATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAA 
               
               
                 AAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCA 
               
               
                 GGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACC 
               
               
                 TCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTA 
               
               
                 TTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGA 
               
               
                 CAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCC 
               
               
                 AGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAAC 
               
               
                 TCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGT 
               
               
                 TTTCTTCAAAAGAGCAGTGGAAGGTAGACAGCACAATTACCTATGTGCTGGAAGGAATGATTGCATCATC 
               
               
                 GATAAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGG 
               
               
                 AAGCTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTC 
               
               
                 TGAAAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTG 
               
               
                 TTGGAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGA 
               
               
                 TCATGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACC 
               
               
                 AGGTTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCA 
               
               
                 TTTGCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTA 
               
               
                 TTAATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGA 
               
               
                 GTTACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGTT 
               
               
                 CCTAAGGACGGTCTGAAGAGCCAAGAGCTATTTGATGAAATTAGAATGACCTACATCAAAGAGCTAGGAA 
               
               
                 AAGCCATTGTCAAGAGGGAAGGAAACTCCAGCCAGAACTGGCAGCGGTTTTATCAACTGACAAAACTCTT 
               
               
                 GGATTCTATGCATGAAGTGGTTGAAAATCTCCTTAACTATTGCTTCCAAACATTTTTGGATAAGACCATG 
               
               
                 AGTATTGAATTCCCCGAGATGTTAGCTGAAATCATCACCAATCAGATACCAAAATATTCAAATGGAAATA 
               
               
                 TCAAAAAACTTCTGTTTCATCAAAAGTGACTGCCTTAATAAGAATGGTTGCCTTAAAGAAAGTCGAATTA 
               
               
                 ATAGCTTTTATTGTATAAACTATCAGTTTGTCCTGTAGAGGTTTTGTTGTTTTATTTTTTATTGTTTTCA 
               
               
                 TCTGTTGTTTTGTTTTAAATACGCACTACATGTGGTTTATAGAGGGCCAAGACTTGGCAACAGAAGCAGT 
               
               
                 TGAGTCGTCATCACTTTTCAGTGATGGGAGAGTAGATGGTGAAATTTATTAGTTAATATATCCCAGAAAT 
               
               
                 TAGAAACCTTAATATGTGGACGTAATCTCCACAGTCAAAGAAGGATGGCACCTAAACCACCAGTGCCCAA 
               
               
                 AGTCTGTGTGATGAACTTTCTCTTCATACTTTTTTTCACAGTTGGCTGGATGAAATTTTCTAGACTTTCT 
               
               
                 GTTGGTGTATCCCCCCCCTGTATAGTTAGGATAGCATTTTTGATTTATGCATGGAAACCTGAAAAAAAGT 
               
               
                 TTACAAGTGTATATCAGAAAAGGGAAGTTGTGCCTTTTATAGCTATTACTGTCTGGTTTTAACAATTTCC 
               
               
                 TTTATATTTAGTGAACTACGCTTGCTCATTTTTTCTTACATAATTTTTTATTCAAGTTATTGTACAGCTG 
               
               
                 TTTAAGATGGGCAGCTAGTTCGTAGCTTTCCCAAATAAACTCTAAACATTAATCAATCATCTGTGTGAAA 
               
               
                 ATGGGTTGGTGCTTCTAACCTGATGGCACTTAGCTATCAGAAGACCACAAAAATTGACTCAAATCTCCAG 
               
               
                 TATTCTTGTCAAAAAAAAAAAAAAAAAAGCTCATATTTTGTATATATCTGCTTCAGTGGAGAATTATATA 
               
               
                 GGTTGTGCAAATTAACAGTCCTAACTGGTATAGAGCACCTAGTCCAGTGACCTGCTGGGTAAACTGTGGA 
               
               
                 TGATGGTTGCAAAAGACTAATTTAAAAAATAACTACCAAGAGGCCCTGTCTGTACCTAACGCCCTATTTT 
               
               
                 TGCAATGGCTATATGGCAAGAAAGCTGGTAAACTATTTGTCTTTCAGGACCTTTTGAAGTAGTTTGTATA 
               
               
                 ACTTCTTAAAAGTTGTGATTCCAGATAACCAGCTGTAACACAGCTGAGAGACTTTTAATCAGACAAAGTA 
               
               
                 ATTCCTCTCACTAAACTTTACCCAAAAACTAAATCTCTAATATGGCAAAAATGGCTAGACACCCATTTTC 
               
               
                 ACATTCCCATCTGTCACCAATTGGTTAATCTTTCCTGATGGTACAGGAAAGCTCAGCTACTGATTTTTGT 
               
               
                 GATTTAGAACTGTATGTCAGACATCCATGTTTGTAAAACTACACATCCCTAATGTGTGCCATAGAGTTTA 
               
               
                 ACACAAGTCCTGTGAATTTCTTCACTGTTGAAAATTATTTTAAACAAAATAGAAGCTGTAGTAGCCCTTT 
               
               
                 CTGTGTGCACCTTACCAACTTTCTGTAAACTCAAAACTTAACATATTTACTAAGCCACAAGAAATTTGAT 
               
               
                 TTCTATTCAAGGTGGCCAAATTATTTGTGTAATAGAAAACTGAAAATCTAATATTAAAAATATGGAACTT 
               
               
                 CTAATATATTTTTATATTTAGTTATAGTTTCAGATATATATCATATTGGTATTCACTAATCTGGGAAGGG 
               
               
                 AAGGGCTACTGCAGCTTTACATGCAATTTATTAAAATGATTGTAAAATAGCTTGTATAGTGTAAAATAAG 
               
               
                 AATGATTTTTAGATGAGATTGTTTTATCATGACATGTTATATATTTTTTGTAGGGGTCAAAGAAATGCTG 
               
               
                 ATGGATAACCTATATGATTTATAGTTTGTACATGCATTCATACAGGCAGCGATGGTCTCAGAAACCAAAC 
               
               
                 AGTTTGCTCTAGGGGAAGAGGGAGATGGAGACTGGTCCTGTGTGCAGTGAAGGTTGCTGAGGCTCTGACC 
               
               
                 CAGTGAGATTACAGAGGAAGTTATCCTCTGCCTCCCATTCTGACCACCCTTCTCATTCCAACAGTGAGTC 
               
               
                 TGTCAGCGCAGGTTTAGTTTACTCAATCTCCCCTTGCACTAAAGTATGTAAAGTATGTAAACAGGAGACA 
               
               
                 GGAAGGTGGTGCTTACATCCTTAAAGGCACCATCTAATAGCGGGTTACTTTCACATACAGCCCTCCCCCA 
               
               
                 GCAGTTGAATGACAACAGAAGCTTCAGAAGTTTGGCAATAGTTTGCATAGAGGTACCAGCAATATGTAAA 
               
               
                 TAGTGCAGAATCTCATAGGTTGCCAATAATACACTAATTCCTTTCTATCCTACAACAAGAGTTTATTTCC 
               
               
                 AAATAAAATGAGGACATGTTTTTGTTTTCTTTGAATGCTTTTTGAATGTTATTTGTTATTTTCAGTATTT 
               
               
                 TGGAGAAATTATTTAATAAAAAAACAATCATTTGCTTTTTGAATGCTCTCTAAAAGGGAATGTAATATTT 
               
               
                 TAAGATGGTGTGTAACCCGGCTGGATAAATTTTTGGTGCCTAAGAAAACTGCTTGAATATTCTTATCAAT 
               
               
                 GACAGTGTTAAGTTTCAAAAAGAGCTTCTAAAACGTAGATTATCATTCCTTTATAGAATGTTATGTGGTT 
               
               
                 AAAACCAGAAAGCACATCTCACACATTAATCTGATTTTCATCCCAACAATCTTGGCGCTCAAAAAATAGA 
               
               
                 ACTCAATGAGAAAAAGAAGATTATGTGCACTTCGTTGTCAATAATAAGTCAACTGATGCTCATCGACAAC 
               
               
                 TATAGGAGGCTTTTCATTAAATGGGAAAAGAAGCTGTGCCCTTTTAGGATACGTGGGGGAAAAGAAAGTC 
               
               
                 ATCTTAATTATGTTTAATTGTGGATTTAAGTGCTATATGGTGGTGCTGTTTGAAAGCAGATTTATTTCCT 
               
               
                 ATGTATGTGTTATCTGGCCATCCCAACCCAAACTGTTGAAGTTTGTAGTAACTTCAGTGAGAGTTGGTTA 
               
               
                 CTCACAACAAATCCTGAAAAGTATTTTTAGTGTTTGTAGGTATTCTGTGGGATACTATACAAGCAGAACT 
               
               
                 GAGGCACTTAGGACATAACACTTTTGGGGTATATATATCCAAATGCCTAAAACTATGGGAGGAAACCTTG 
               
               
                 GCCACCCCAAAAGGAAAACTAACATGATTTGTGTCTATGAAGTGCTGGATAATTAGCATGGGATGAGCTC 
               
               
                 TGGGCATGCCATGAAGGAAAGCCACGCTCCCTTCAGAATTCAGAGGCAGGGAGCAATTCCAGTTTCACCT 
               
               
                 AAGTCTCATAATTTTAGTTCCCTTTTAAAAACCCTGAAAACTACATCACCATGGAATGAAAAATATTGTT 
               
               
                 ATACAATACATTGATCTGTCAAACTTCCAGAACCATGGTAGCCTTCAGTGAGATTTCCATCTTGGCTGGT 
               
               
                 CACTCCCTGACTGTAGCTGTAGGTGAATGTGTTTTTGTGTGTGTGTGTCTGGTTTTAGTGTCAGAAGGGA 
               
               
                 AATAAAAGTGTAAGGAGGACACTTTAAACCCTTTGGGTGGAGTTTCGTAATTTCCCAGACTATTTTCAAG 
               
               
                 CAACCTGGTCCACCCAGGATTAGTGACCAGGTTTTCAGGAAAGGATTTGCTTCTCTCTAGAAAATGTCTG 
               
               
                 AAAGGATTTTATTTTCTGATGAAAGGCTGTATGAAAATACCCTCCTCAAATAACTTGCTTAACTACATAT 
               
               
                 AGATTCAAGTGTGTCAATATTCTATTTTGTATATTAAATGCTATATAATGGGGACAAATCTATATTATAC 
               
               
                 TGTGTATGGCATTATTAAGAAGCTTTTTCATTATTTTTTATCACAGTAATTTTAAAATGTGTAAAAATTA 
               
               
                 AAACCAGTGACTCCTGTTTAAAAATAAAAGTTGTAGTTTTTTATTCATGCTGAATAATAATCTGTAGTTA 
               
               
                 AAAAAAAAGTGTCTTTTTACCTACGCAGTGAAATGTCAGACTGTAAAACCTTGTGTGGAAATGTTTAACT 
               
               
                 TTTATTTTTTCATTTAAATTTGCTGTTCTGGTATTACCAAACCACACATTTGTACCGAATTGGCAGTAAA 
               
               
                 TGTTAGCCATTTACAGCAATGCCAAATATGGAGAAACATCATAATAAAAAAATCTGCTTTTTCATTA 
               
               
                   
               
               
                 SEQ ID NO: 21 Human GR Transcript Variant 8 mRNA Sequence (NCBI Reference Sequence: 
               
               
                 NM_001204265.1) 
               
               
                 GGCGCCGCCTCCACCCGCTCCCCGCTCGGTCCCGCTCGCTCGCCCAGGCCGGGCTGCCCTTTCGCGTGTC 
               
               
                 CGCGCTCTCTTCCCTCCGCCGCCGCCTCCTCCATTTTGCGAGCTCGTGTCTGTGACGGGAGCCCGAGTCA 
               
               
                 CCGCCTGCCCGTCGGGGACGGATTCTGTGGGTGGAAGGAGACGCCGCAGCCGGAGCGGCCGAAGCAGCTG 
               
               
                 GGACCGGGACGGGGCACGCGCGCCCGGAACCTCGACCCGCGGAGCCCGGCGCGGGGCGGAGGGCTGGCTT 
               
               
                 GTCAGCTGGGCAATGGGAGACTTTCTTAAATAGGGGCTCTCCCCCCACCCATGGAGAAAGGGGCGGCTGT 
               
               
                 TTACTTCCTTTTTTTAGAAAAAAAAAATATATTTCCCTCCTGCTCCTTCTGCGTTCACAAGCTAAGTTGT 
               
               
                 TTATCTCGGCTGCGGCGGGAACTGCGGACGGTGGCGGGCGAGCGGCTCCTCTGCCAGAGTTGATATTCAC 
               
               
                 TGATGGACTCCAAAGAATCATTAACTCCTGGTAGAGAAGAAAACCCCAGCAGTGTGCTTGCTCAGGAGAG 
               
               
                 GGGAGATGTGATGGACTTCTATAAAACCCTAAGAGGAGGAGCTACTGTGAAGGTTTCTGCGTCTTCACCC 
               
               
                 TCACTGGCTGTCGCTTCTCAATCAGACTCCAAGCAGCGAAGACTTTTGGTTGATTTTCCAAAAGGCTCAG 
               
               
                 TAAGCAATGCGCAGCAGCCAGATCTGTCCAAAGCAGTTTCACTCTCAATGGGACTGTATATGGGAGAGAC 
               
               
                 AGAAACAAAAGTGATGGGAAATGACCTGGGATTCCCACAGCAGGGCCAAATCAGCCTTTCCTCGGGGGAA 
               
               
                 ACAGACTTAAAGCTTTTGGAAGAAAGCATTGCAAACCTCAATAGGTCGACCAGTGTTCCAGAGAACCCCA 
               
               
                 AGAGTTCAGCATCCACTGCTGTGTCTGCTGCCCCCACAGAGAAGGAGTTTCCAAAAACTCACTCTGATGT 
               
               
                 ATCTTCAGAACAGCAACATTTGAAGGGCCAGACTGGCACCAACGGTGGCAATGTGAAATTGTATACCACA 
               
               
                 GACCAAAGCACCTTTGACATTTTGCAGGATTTGGAGTTTTCTTCTGGGTCCCCAGGTAAAGAGACGAATG 
               
               
                 AGAGTCCTTGGAGATCAGACCTGTTGATAGATGAAAACTGTTTGCTTTCTCCTCTGGCGGGAGAAGACGA 
               
               
                 TTCATTCCTTTTGGAAGGAAACTCGAATGAGGACTGCAAGCCTCTCATTTTACCGGACACTAAACCCAAA 
               
               
                 ATTAAGGATAATGGAGATCTGGTTTTGTCAAGCCCCAGTAATGTAACACTGCCCCAAGTGAAAACAGAAA 
               
               
                 AAGAAGATTTCATCGAACTCTGCACCCCTGGGGTAATTAAGCAAGAGAAACTGGGCACAGTTTACTGTCA 
               
               
                 GGCAAGCTTTCCTGGAGCAAATATAATTGGTAATAAAATGTCTGCCATTTCTGTTCATGGTGTGAGTACC 
               
               
                 TCTGGAGGACAGATGTACCACTATGACATGAATACAGCATCCCTTTCTCAACAGCAGGATCAGAAGCCTA 
               
               
                 TTTTTAATGTCATTCCACCAATTCCCGTTGGTTCCGAAAATTGGAATAGGTGCCAAGGATCTGGAGATGA 
               
               
                 CAACTTGACTTCTCTGGGGACTCTGAACTTCCCTGGTCGAACAGTTTTTTCTAATGGCTATTCAAGCCCC 
               
               
                 AGCATGAGACCAGATGTAAGCTCTCCTCCATCCAGCTCCTCAACAGCAACAACAGGACCACCTCCCAAAC 
               
               
                 TCTGCCTGGTGTGCTCTGATGAAGCTTCAGGATGTCATTATGGAGTCTTAACTTGTGGAAGCTGTAAAGT 
               
               
                 TTTCTTCAAAAGAGCAGTGGAAGGACAGCACAATTACCTATGTGCTGGAAGGAATGATTGCATCATCGAT 
               
               
                 AAAATTCGAAGAAAAAACTGCCCAGCATGCCGCTATCGAAAATGTCTTCAGGCTGGAATGAACCTGGAAG 
               
               
                 CTCGAAAAACAAAGAAAAAAATAAAAGGAATTCAGCAGGCCACTACAGGAGTCTCACAAGAAACCTCTGA 
               
               
                 AAATCCTGGTAACAAAACAATAGTTCCTGCAACGTTACCACAACTCACCCCTACCCTGGTGTCACTGTTG 
               
               
                 GAGGTTATTGAACCTGAAGTGTTATATGCAGGATATGATAGCTCTGTTCCAGACTCAACTTGGAGGATCA 
               
               
                 TGACTACGCTCAACATGTTAGGAGGGCGGCAAGTGATTGCAGCAGTGAAATGGGCAAAGGCAATACCAGG 
               
               
                 TTTCAGGAACTTACACCTGGATGACCAAATGACCCTACTGCAGTACTCCTGGATGTTTCTTATGGCATTT 
               
               
                 GCTCTGGGGTGGAGATCATATAGACAATCAAGTGCAAACCTGCTGTGTTTTGCTCCTGATCTGATTATTA 
               
               
                 ATGAGCAGAGAATGACTCTACCCTGCATGTACGACCAATGTAAACACATGCTGTATGTTTCCTCTGAGTT 
               
               
                 ACACAGGCTTCAGGTATCTTATGAAGAGTATCTCTGTATGAAAACCTTACTGCTTCTCTCTTCAGGTTGG 
               
               
                 TAGAACACCTTTTCACCTTATGTCAAAAGCATGAAATATGAAGGCCTAGAAACAAAGGTTAATTTATATA 
               
               
                 CATAGTACTAATAATTATACCAAGTCTACTATTATTTCCTACTAGTCAGATGATTTTTATGAATGTAAAA 
               
               
                 TATTAGAAAGGCACAGTAAGTGACACCAAGATTAATAAGACAAATAGGTATGGCAGAAACAGAGAGGTAT 
               
               
                 ATGAGCTGCATAGGGATCTCTGTTGATAAGAATCTGTGTAGACTTTTTTCTCCTTCCTTCCTTTGATCTT 
               
               
                 TGATCATGGGAAGACATGGAAAAAGAAAGCTAACTACAGTGATTTTGTCCACTACACTGTTATTTGGTTA 
               
               
                 AAAATTTTAGTTTCCTAATGAGTATTAGCATGTATGAGAAATTATGGGAGAAAAAGGCGCATCCTAGAAA 
               
               
                 AGGTGTGCTTAATTACTATTGGGGATTGGTTAACATAGCATGGGAGCTGGATTGTCAGAGATTCATTATC 
               
               
                 TAGAAAATGGCAACAAGAGTTTATAAAACGAACTTCTGTGAGATTACTTTTTAGCTAGCAAAGACAAAGA 
               
               
                 TGTCCTTCAGTAGGTGAAGTGATAAACTATGATACATCCAGATGATGGAATACTATTGAGGACTAAAAAG 
               
               
                 AAATAAGCTGTCAAGCCATGAAAACACATGGAGGGACGTTAAATGCATATTACTAAGTGAAAAAAGCTAA 
               
               
                 TCTGAAAGGGCTACATACTGTGTGATTCTAACTATATAACATTCCATAAAAGGCAAAACTGTGAAGACAG 
               
               
                 CAAAAAAAAATCAGCGGTTGCCAGGGTTTAGAAGGAAGGGAGGGATAAATGTGCAGAGCACAGAGGATTT 
               
               
                 TTAGGGCAGTGAAAATACTTCGTATGATACTACAATGGTGGAAACATGTCATTATACATTTATCCAAACC 
               
               
                 CAAAGAATGTCCACCACCAAGAGTGAACCCTCAACTATGGACTTTGGGTGATGATGTGTGGGACAGGAGG 
               
               
                 TATATGAAAAATCTCTGTACCTTCCTCCCAATTTTGCTGTGAACTTAAAACTGCTCTAAAAAAAGTCTTT 
               
               
                 TTTAAAAAAAGCTCTATGAACTAGTTGGTATTATAAACCTTAGGCCATTTCAAGTAAAAATTACATATCA 
               
               
                 ATGTTTATTAAATACTGAGTTAATAGCTGAATACCTCTTTCATATACAAATAAGTACATTTGCAATTTTT 
               
               
                 TAAAAAGTCTTAATTCCATTAGTAACTGTGGTTTCATAGTTGCCAAATAACTGTAAGCTATGGATGTTGC 
               
               
                 ACAAGACTGTGATTTTATTTAATCATTTCATATCTATTTAAACATTTCCAAAGCGCACATTCATCTTAAT 
               
               
                 GTTTTCACACTATTTTTGCTCAACAAAAAGTTATTTTATGTTAATGGATATAAGAAGTATTAATAATATT 
               
               
                 TCAGTCAAGGCAAGAGAACCCGATAAAGATCATTGCTAGAGACGTTTAATGTTACCTGTAGCGGTACACT 
               
               
                 TGTTAAAGAAGTGATTAAGCAGTTACATAAAATTCTGATCATAGCTTTGATTGATACCATGAAGGTATAA 
               
               
                 TTCAGTGCCTGGATACTAACAACTTTACTTGTTTAAAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 22 Human serine/threonine-protein kinase Sgk1 isoform 1 Protein Sequence (NCBI 
               
               
                 Reference Sequence: NP_005618.2) 
               
               
                 MTVKTEAAKGTLTYSRMRGMVAILIAFMKQRRMGLNDFIQKIANNSYACKHPEVQSILKISQPQEPELMN 
               
               
                 ANPSPPPSPSQQINLGPSSNPHAKPSDFHFLKVIGKGSFGKVLLARHKAEEVFYAVKVLQKKAILKKKEE 
               
               
                 KHIMSERNVLLKNVKHPFLVGLHFSFQTADKLYFVLDYINGGELFYHLQRERCFLEPRARFYAAEIASAL 
               
               
                 GYLHSLNIVYRDLKPENILLDSQGHIVLTDFGLCKENIEHNSTTSTFCGTPEYLAPEVLHKQPYDRTVDW 
               
               
                 WCLGAVLYEMLYGLPPFYSRNTAEMYDNILNKPLQLKPNITNSARHLLEGLLQKDRTKRLGAKDDFMEIK 
               
               
                 SHVFFSLINWDDLINKKITPPFNPNVSGPNDLRHFDPEFTEEPVPNSIGKSPDSVLVTASVKEAAEAFLG 
               
               
                 FSYAPPTDSFL 
               
               
                   
               
               
                 SEQ ID NO: 23 Human serine/threonine-protein kinase Sgk1 isoform 2 Protein Sequence (NCBI 
               
               
                 Reference Sequence: NP_001137148.1) 
               
               
                 MVNKDMNGFPVKKCSAFQFFKKRVRRWIKSPMVSVDKHQSPSLKYTGSSMVHIPPGEPDFESSLCQTCLG 
               
               
                 EHAFQRGVLPQENESCSWETQSGCEVREPCNHANILTKPDPRTFWTNDDPAFMKQRRMGLNDFIQKIANN 
               
               
                 SYACKHPEVQSILKISQPQEPELMNANPSPPPSPSQQINLGPSSNPHAKPSDFHFLKVIGKGSFGKVLLA 
               
               
                 RHKAEEVFYAVKVLQKKAILKKKEEKHIMSERNVLLKNVKHPFLVGLHFSFQTADKLYFVLDYINGGELF 
               
               
                 YHLQRERCFLEPRARFYAAEIASALGYLHSLNIVYRDLKPENILLDSQGHIVLTDFGLCKENIEHNSTTS 
               
               
                 TFCGTPEYLAPEVLHKQPYDRTVDWWCLGAVLYEMLYGLPPFYSRNTAEMYDNILNKPLQLKPNITNSAR 
               
               
                 HLLEGLLQKDRTKRLGAKDDFMEIKSHVFFSLINWDDLINKKITPPFNPNVSGPNDLRHFDPEFTEEPVP 
               
               
                 NSIGKSPDSVLVTASVKEAAEAFLGFSYAPPTDSFL 
               
               
                   
               
               
                 SEQ ID NO: 24 Human serine/threonine-protein kinase Sgk1 isoform 3 Protein Sequence (NCBI 
               
               
                 Reference Sequence: NP_001137149.1) 
               
               
                 MSSQSSSLSEACSREAYSSHNWALPPASRSNPQPAYPWATRRMKEEAIKPPLKAFMKQRRMGLNDFIQKI 
               
               
                 ANNSYACKHPEVQSILKISQPQEPELMNANPSPPPSPSQQINLGPSSNPHAKPSDFHFLKVIGKGSFGKV 
               
               
                 LLARHKAEEVFYAVKVLQKKAILKKKEEKHIMSERNVLLKNVKHPFLVGLHFSFQTADKLYFVLDYINGG 
               
               
                 ELFYHLQRERCFLEPRARFYAAEIASALGYLHSLNIVYRDLKPENILLDSQGHIVLTDFGLCKENIEHNS 
               
               
                 TTSTFCGTPEYLAPEVLHKQPYDRTVDWWCLGAVLYEMLYGLPPFYSRNTAEMYDNILNKPLQLKPNITN 
               
               
                 SARHLLEGLLQKDRTKRLGAKDDFMEIKSHVFFSLINWDDLINKKITPPFNPNVSGPNDLRHFDPEFTEE 
               
               
                 PVPNSIGKSPDSVLVTASVKEAAEAFLGFSYAPPTDSFL 
               
               
                   
               
               
                 SEQ ID NO: 25 Human serine/threonine-protein kinase Sgk1 isoform 4 Protein Sequence (NCBI 
               
               
                 Reference Sequence: NP_001137150.1) 
               
               
                 MGEMQGALARARLESLLRPRHKKRAEAQKRSESFLLSGLAFMKQRRMGLNDFIQKIANNSYACKHPEVQS 
               
               
                 ILKISQPQEPELMNANPSPPPSPSQQINLGPSSNPHAKPSDFHFLKVIGKGSFGKVLLARHKAEEVFYAV 
               
               
                 KVLQKKAILKKKEEKHIMSERNVLLKNVKHPFLVGLHFSFQTADKLYFVLDYINGGELFYHLQRERCFLE 
               
               
                 PRARFYAAEIASALGYLHSLNIVYRDLKPENILLDSQGHIVLTDFGLCKENIEHNSTTSTFCGTPEYLAP 
               
               
                 EVLHKQPYDRTVDWWCLGAVLYEMLYGLPPFYSRNTAEMYDNILNKPLQLKPNITNSARHLLEGLLQKDR 
               
               
                 TKRLGAKDDFMEIKSHVFFSLINWDDLINKKITPPFNPNVSGPNDLRHFDPEFTEEPVPNSIGKSPDSVL 
               
               
                 VTASVKEAAEAFLGFSYAPPTDSFL 
               
               
                   
               
               
                 SEQ ID NO: 26 Human SGK1 Transcript Variant 1 mRNA Sequence (NCBI Reference 
               
               
                 Sequence: NM_005627.3) 
               
               
                 TTTTTTATAAGGCCGAGCGCGCGGCCTGGCGCAGCATACGCCGAGCCGGTCTTTGAGCGCTAACGTCTTT 
               
               
                 CTGTCTCCCCGCGGTGGTGATGACGGTGAAAACTGAGGCTGCTAAGGGCACCCTCACTTACTCCAGGATG 
               
               
                 AGGGGCATGGTGGCAATTCTCATCGCTTTCATGAAGCAGAGGAGGATGGGTCTGAACGACTTTATTCAGA 
               
               
                 AGATTGCCAATAACTCCTATGCATGCAAACACCCTGAAGTTCAGTCCATCTTGAAGATCTCCCAACCTCA 
               
               
                 GGAGCCTGAGCTTATGAATGCCAACCCTTCTCCTCCACCAAGTCCTTCTCAGCAAATCAACCTTGGCCCG 
               
               
                 TCGTCCAATCCTCATGCTAAACCATCTGACTTTCACTTCTTGAAAGTGATCGGAAAGGGCAGTTTTGGAA 
               
               
                 AGGTTCTTCTAGCAAGACACAAGGCAGAAGAAGTGTTCTATGCAGTCAAAGTTTTACAGAAGAAAGCAAT 
               
               
                 CCTGAAAAAGAAAGAGGAGAAGCATATTATGTCGGAGCGGAATGTTCTGTTGAAGAATGTGAAGCACCCT 
               
               
                 TTCCTGGTGGGCCTTCACTTCTCTTTCCAGACTGCTGACAAATTGTACTTTGTCCTAGACTACATTAATG 
               
               
                 GTGGAGAGTTGTTCTACCATCTCCAGAGGGAACGCTGCTTCCTGGAACCACGGGCTCGTTTCTATGCTGC 
               
               
                 TGAAATAGCCAGTGCCTTGGGCTACCTGCATTCACTGAACATCGTTTATAGAGACTTAAAACCAGAGAAT 
               
               
                 ATTTTGCTAGATTCACAGGGACACATTGTCCTTACTGACTTCGGACTCTGCAAGGAGAACATTGAACACA 
               
               
                 ACAGCACAACATCCACCTTCTGTGGCACGCCGGAGTATCTCGCACCTGAGGTGCTTCATAAGCAGCCTTA 
               
               
                 TGACAGGACTGTGGACTGGTGGTGCCTGGGAGCTGTCTTGTATGAGATGCTGTATGGCCTGCCGCCTTTT 
               
               
                 TATAGCCGAAACACAGCTGAAATGTACGACAACATTCTGAACAAGCCTCTCCAGCTGAAACCAAATATTA 
               
               
                 CAAATTCCGCAAGACACCTCCTGGAGGGCCTCCTGCAGAAGGACAGGACAAAGCGGCTCGGGGCCAAGGA 
               
               
                 TGACTTCATGGAGATTAAGAGTCATGTCTTCTTCTCCTTAATTAACTGGGATGATCTCATTAATAAGAAG 
               
               
                 ATTACTCCCCCTTTTAACCCAAATGTGAGTGGGCCCAACGACCTACGGCACTTTGACCCCGAGTTTACCG 
               
               
                 AAGAGCCTGTCCCCAACTCCATTGGCAAGTCCCCTGACAGCGTCCTCGTCACAGCCAGCGTCAAGGAAGC 
               
               
                 TGCCGAGGCTTTCCTAGGCTTTTCCTATGCGCCTCCCACGGACTCTTTCCTCTGAACCCTGTTAGGGCTT 
               
               
                 GGTTTTAAAGGATTTTATGTGTGTTTCCGAATGTTTTAGTTAGCCTTTTGGTGGAGCCGCCAGCTGACAG 
               
               
                 GACATCTTACAAGAGAATTTGCACATCTCTGGAAGCTTAGCAATCTTATTGCACACTGTTCGCTGGAAGC 
               
               
                 TTTTTGAAGAGCACATTCTCCTCAGTGAGCTCATGAGGTTTTCATTTTTATTCTTCCTTCCAACGTGGTG 
               
               
                 CTATCTCTGAAACGAGCGTTAGAGTGCCGCCTTAGACGGAGGCAGGAGTTTCGTTAGAAAGCGGACGCTG 
               
               
                 TTCTAAAAAAGGTCTCCTGCAGATCTGTCTGGGCTGTGATGACGAATATTATGAAATGTGCCTTTTCTGA 
               
               
                 AGAGATTGTGTTAGCTCCAAAGCTTTTCCTATCGCAGTGTTTCAGTTCTTTATTTTCCCTTGTGGATATG 
               
               
                 CTGTGTGAACCGTCGTGTGAGTGTGGTATGCCTGATCACAGATGGATTTTGTTATAAGCATCAATGTGAC 
               
               
                 ACTTGCAGGACACTACAACGTGGGACATTGTTTGTTTCTTCCATATTTGGAAGATAAATTTATGTGTAGA 
               
               
                 CTTTTTTGTAAGATACGGTTAATAACTAAAATTTATTGAAATGGTCTTGCAATGACTCGTATTCAGATGC 
               
               
                 TTAAAGAAAGCATTGCTGCTACAAATATTTCTATTTTTAGAAAGGGTTTTTATGGACCAATGCCCCAGTT 
               
               
                 GTCAGTCAGAGCCGTTGGTGTTTTTCATTGTTTAAAATGTCACCTGTAAAATGGGCATTATTTATGTTTT 
               
               
                 TTTTTTTGCATTCCTGATAATTGTATGTATTGTATAAAGAACGTCTGTACATTGGGTTATAACACTAGTA 
               
               
                 TATTTAAACTTACAGGCTTATTTGTAATGTAAACCACCATTTTAATGTACTGTAATTAACATGGTTATAA 
               
               
                 TACGTACAATCCTTCCCTCATCCCATCACACAACTTTTTTTGTGTGTGATAAACTGATTTTGGTTTGCAA 
               
               
                 TAAAACCTTGAAAAATATTTACATATAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 27 Human SGK1 Transcript Variant 2 mRNA Sequence (NCBI Reference 
               
               
                 Sequence: NM_001143676.1) 
               
               
                 AGATATTCATGAACCGTTGCTTCTTCCAGCCTCGCCTTCTCGCTCCCTCTGCCTTTCTGGCGCTGTTCTC 
               
               
                 CCTCCCTCCCTCTGGCTTCTGCTCTTTCTTACTCCTTCTCTCAGCTGCTTAACTACAGCTCCCACTGGAA 
               
               
                 CTTGCACAATCAAAAACAACTCTCCTCTCTCAAGCCGCCTCCAGGAGCGCATCACCTGGAGAAGAGCGAC 
               
               
                 TCGCTCCCCGCGCCGGCCGCGGAAGAGCAGCCAGGTAGCTGGGGGCGGGGAGGCGTACCCTTCTCCCGCT 
               
               
                 CGGTAAGAGCCACAGCATCTCCCCGGAGATTGGCCGTATCCCACCGTCCGGCCCCCAGGGTCCTGCAGCG 
               
               
                 GTGATGCATATGTTTCGGAGCAATGATGGAAGGAGAAAAGCCGCTGTCGGTGGCAACTGAAAGTGGGGAG 
               
               
                 AGGTTGCTGCAGTAGCTGGTGCTGCAGAATGCGCGAGTGAAGAACTGAGCCCCGCTAGATTCTCCATCCC 
               
               
                 GCTCAGTCTTCATTAACTGTCTGCAGGAGGTAAACCGGGGAAACAGATATGCACTAACCAGGCGGGTGCC 
               
               
                 AACCTGGATCTATAACTGTGAATTCCCCACGGTGGAAAATGGTAAACAAAGACATGAATGGATTCCCAGT 
               
               
                 CAAGAAATGCTCAGCCTTCCAATTTTTTAAGAAGCGGGTACGAAGGTGGATCAAGAGCCCAATGGTCAGT 
               
               
                 GTGGACAAGCATCAGAGTCCCAGCCTGAAGTACACCGGCTCCTCCATGGTGCACATCCCTCCAGGGGAGC 
               
               
                 CAGACTTCGAGTCTTCCTTGTGTCAAACATGCCTGGGTGAACATGCTTTCCAAAGAGGGGTTCTCCCTCA 
               
               
                 GGAGAACGAGTCATGTTCATGGGAAACTCAATCTGGGTGTGAAGTGAGAGAGCCATGTAATCATGCCAAC 
               
               
                 ATCCTGACCAAGCCCGATCCAAGAACCTTCTGGACTAATGATGATCCAGCTTTCATGAAGCAGAGGAGGA 
               
               
                 TGGGTCTGAACGACTTTATTCAGAAGATTGCCAATAACTCCTATGCATGCAAACACCCTGAAGTTCAGTC 
               
               
                 CATCTTGAAGATCTCCCAACCTCAGGAGCCTGAGCTTATGAATGCCAACCCTTCTCCTCCACCAAGTCCT 
               
               
                 TCTCAGCAAATCAACCTTGGCCCGTCGTCCAATCCTCATGCTAAACCATCTGACTTTCACTTCTTGAAAG 
               
               
                 TGATCGGAAAGGGCAGTTTTGGAAAGGTTCTTCTAGCAAGACACAAGGCAGAAGAAGTGTTCTATGCAGT 
               
               
                 CAAAGTTTTACAGAAGAAAGCAATCCTGAAAAAGAAAGAGGAGAAGCATATTATGTCGGAGCGGAATGTT 
               
               
                 CTGTTGAAGAATGTGAAGCACCCTTTCCTGGTGGGCCTTCACTTCTCTTTCCAGACTGCTGACAAATTGT 
               
               
                 ACTTTGTCCTAGACTACATTAATGGTGGAGAGTTGTTCTACCATCTCCAGAGGGAACGCTGCTTCCTGGA 
               
               
                 ACCACGGGCTCGTTTCTATGCTGCTGAAATAGCCAGTGCCTTGGGCTACCTGCATTCACTGAACATCGTT 
               
               
                 TATAGAGACTTAAAACCAGAGAATATTTTGCTAGATTCACAGGGACACATTGTCCTTACTGACTTCGGAC 
               
               
                 TCTGCAAGGAGAACATTGAACACAACAGCACAACATCCACCTTCTGTGGCACGCCGGAGTATCTCGCACC 
               
               
                 TGAGGTGCTTCATAAGCAGCCTTATGACAGGACTGTGGACTGGTGGTGCCTGGGAGCTGTCTTGTATGAG 
               
               
                 ATGCTGTATGGCCTGCCGCCTTTTTATAGCCGAAACACAGCTGAAATGTACGACAACATTCTGAACAAGC 
               
               
                 CTCTCCAGCTGAAACCAAATATTACAAATTCCGCAAGACACCTCCTGGAGGGCCTCCTGCAGAAGGACAG 
               
               
                 GACAAAGCGGCTCGGGGCCAAGGATGACTTCATGGAGATTAAGAGTCATGTCTTCTTCTCCTTAATTAAC 
               
               
                 TGGGATGATCTCATTAATAAGAAGATTACTCCCCCTTTTAACCCAAATGTGAGTGGGCCCAACGACCTAC 
               
               
                 GGCACTTTGACCCCGAGTTTACCGAAGAGCCTGTCCCCAACTCCATTGGCAAGTCCCCTGACAGCGTCCT 
               
               
                 CGTCACAGCCAGCGTCAAGGAAGCTGCCGAGGCTTTCCTAGGCTTTTCCTATGCGCCTCCCACGGACTCT 
               
               
                 TTCCTCTGAACCCTGTTAGGGCTTGGTTTTAAAGGATTTTATGTGTGTTTCCGAATGTTTTAGTTAGCCT 
               
               
                 TTTGGTGGAGCCGCCAGCTGACAGGACATCTTACAAGAGAATTTGCACATCTCTGGAAGCTTAGCAATCT 
               
               
                 TATTGCACACTGTTCGCTGGAAGCTTTTTGAAGAGCACATTCTCCTCAGTGAGCTCATGAGGTTTTCATT 
               
               
                 TTTATTCTTCCTTCCAACGTGGTGCTATCTCTGAAACGAGCGTTAGAGTGCCGCCTTAGACGGAGGCAGG 
               
               
                 AGTTTCGTTAGAAAGCGGACGCTGTTCTAAAAAAGGTCTCCTGCAGATCTGTCTGGGCTGTGATGACGAA 
               
               
                 TATTATGAAATGTGCCTTTTCTGAAGAGATTGTGTTAGCTCCAAAGCTTTTCCTATCGCAGTGTTTCAGT 
               
               
                 TCTTTATTTTCCCTTGTGGATATGCTGTGTGAACCGTCGTGTGAGTGTGGTATGCCTGATCACAGATGGA 
               
               
                 TTTTGTTATAAGCATCAATGTGACACTTGCAGGACACTACAACGTGGGACATTGTTTGTTTCTTCCATAT 
               
               
                 TTGGAAGATAAATTTATGTGTAGACTTTTTTGTAAGATACGGTTAATAACTAAAATTTATTGAAATGGTC 
               
               
                 TTGCAATGACTCGTATTCAGATGCTTAAAGAAAGCATTGCTGCTACAAATATTTCTATTTTTAGAAAGGG 
               
               
                 TTTTTATGGACCAATGCCCCAGTTGTCAGTCAGAGCCGTTGGTGTTTTTCATTGTTTAAAATGTCACCTG 
               
               
                 TAAAATGGGCATTATTTATGTTTTTTTTTTTGCATTCCTGATAATTGTATGTATTGTATAAAGAACGTCT 
               
               
                 GTACATTGGGTTATAACACTAGTATATTTAAACTTACAGGCTTATTTGTAATGTAAACCACCATTTTAAT 
               
               
                 GTACTGTAATTAACATGGTTATAATACGTACAATCCTTCCCTCATCCCATCACACAACTTTTTTTGTGTG 
               
               
                 TGATAAACTGATTTTGGTTTGCAATAAAACCTTGAAAAATATTTACATATAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 28 Human SGK1 Transcript Variant 3 mRNA Sequence (NCBI Reference 
               
               
                 Sequence: NM_001143677.1) 
               
               
                 AAGTGGGGTTCATAACAGAACAGGGATAGCCGTCTCTGGCTCGTGCTCTCATGTCATCTCAGAGTTCCAG 
               
               
                 CTTATCAGAGGCATGTAGCAGGGAGGCTTATTCCAGCCATAACTGGGCTCTACCTCCAGCCTCCAGAAGT 
               
               
                 AATCCCCAACCTGCATATCCTTGGGCAACCCGAAGAATGAAAGAAGAAGCTATAAAACCCCCTTTGAAAG 
               
               
                 CTTTCATGAAGCAGAGGAGGATGGGTCTGAACGACTTTATTCAGAAGATTGCCAATAACTCCTATGCATG 
               
               
                 CAAACACCCTGAAGTTCAGTCCATCTTGAAGATCTCCCAACCTCAGGAGCCTGAGCTTATGAATGCCAAC 
               
               
                 CCTTCTCCTCCACCAAGTCCTTCTCAGCAAATCAACCTTGGCCCGTCGTCCAATCCTCATGCTAAACCAT 
               
               
                 CTGACTTTCACTTCTTGAAAGTGATCGGAAAGGGCAGTTTTGGAAAGGTTCTTCTAGCAAGACACAAGGC 
               
               
                 AGAAGAAGTGTTCTATGCAGTCAAAGTTTTACAGAAGAAAGCAATCCTGAAAAAGAAAGAGGAGAAGCAT 
               
               
                 ATTATGTCGGAGCGGAATGTTCTGTTGAAGAATGTGAAGCACCCTTTCCTGGTGGGCCTTCACTTCTCTT 
               
               
                 TCCAGACTGCTGACAAATTGTACTTTGTCCTAGACTACATTAATGGTGGAGAGTTGTTCTACCATCTCCA 
               
               
                 GAGGGAACGCTGCTTCCTGGAACCACGGGCTCGTTTCTATGCTGCTGAAATAGCCAGTGCCTTGGGCTAC 
               
               
                 CTGCATTCACTGAACATCGTTTATAGAGACTTAAAACCAGAGAATATTTTGCTAGATTCACAGGGACACA 
               
               
                 TTGTCCTTACTGACTTCGGACTCTGCAAGGAGAACATTGAACACAACAGCACAACATCCACCTTCTGTGG 
               
               
                 CACGCCGGAGTATCTCGCACCTGAGGTGCTTCATAAGCAGCCTTATGACAGGACTGTGGACTGGTGGTGC 
               
               
                 CTGGGAGCTGTCTTGTATGAGATGCTGTATGGCCTGCCGCCTTTTTATAGCCGAAACACAGCTGAAATGT 
               
               
                 ACGACAACATTCTGAACAAGCCTCTCCAGCTGAAACCAAATATTACAAATTCCGCAAGACACCTCCTGGA 
               
               
                 GGGCCTCCTGCAGAAGGACAGGACAAAGCGGCTCGGGGCCAAGGATGACTTCATGGAGATTAAGAGTCAT 
               
               
                 GTCTTCTTCTCCTTAATTAACTGGGATGATCTCATTAATAAGAAGATTACTCCCCCTTTTAACCCAAATG 
               
               
                 TGAGTGGGCCCAACGACCTACGGCACTTTGACCCCGAGTTTACCGAAGAGCCTGTCCCCAACTCCATTGG 
               
               
                 CAAGTCCCCTGACAGCGTCCTCGTCACAGCCAGCGTCAAGGAAGCTGCCGAGGCTTTCCTAGGCTTTTCC 
               
               
                 TATGCGCCTCCCACGGACTCTTTCCTCTGAACCCTGTTAGGGCTTGGTTTTAAAGGATTTTATGTGTGTT 
               
               
                 TCCGAATGTTTTAGTTAGCCTTTTGGTGGAGCCGCCAGCTGACAGGACATCTTACAAGAGAATTTGCACA 
               
               
                 TCTCTGGAAGCTTAGCAATCTTATTGCACACTGTTCGCTGGAAGCTTTTTGAAGAGCACATTCTCCTCAG 
               
               
                 TGAGCTCATGAGGTTTTCATTTTTATTCTTCCTTCCAACGTGGTGCTATCTCTGAAACGAGCGTTAGAGT 
               
               
                 GCCGCCTTAGACGGAGGCAGGAGTTTCGTTAGAAAGCGGACGCTGTTCTAAAAAAGGTCTCCTGCAGATC 
               
               
                 TGTCTGGGCTGTGATGACGAATATTATGAAATGTGCCTTTTCTGAAGAGATTGTGTTAGCTCCAAAGCTT 
               
               
                 TTCCTATCGCAGTGTTTCAGTTCTTTATTTTCCCTTGTGGATATGCTGTGTGAACCGTCGTGTGAGTGTG 
               
               
                 GTATGCCTGATCACAGATGGATTTTGTTATAAGCATCAATGTGACACTTGCAGGACACTACAACGTGGGA 
               
               
                 CATTGTTTGTTTCTTCCATATTTGGAAGATAAATTTATGTGTAGACTTTTTTGTAAGATACGGTTAATAA 
               
               
                 CTAAAATTTATTGAAATGGTCTTGCAATGACTCGTATTCAGATGCTTAAAGAAAGCATTGCTGCTACAAA 
               
               
                 TATTTCTATTTTTAGAAAGGGTTTTTATGGACCAATGCCCCAGTTGTCAGTCAGAGCCGTTGGTGTTTTT 
               
               
                 CATTGTTTAAAATGTCACCTGTAAAATGGGCATTATTTATGTTTTTTTTTTTGCATTCCTGATAATTGTA 
               
               
                 TGTATTGTATAAAGAACGTCTGTACATTGGGTTATAACACTAGTATATTTAAACTTACAGGCTTATTTGT 
               
               
                 AATGTAAACCACCATTTTAATGTACTGTAATTAACATGGTTATAATACGTACAATCCTTCCCTCATCCCA 
               
               
                 TCACACAACTTTTTTTGTGTGTGATAAACTGATTTTGGTTTGCAATAAAACCTTGAAAAATATTTACATA 
               
               
                 TAAAAAAAA 
               
               
                   
               
               
                 SEQ ID NO: 29 Human SGK1 Transcript Variant 4 mRNA Sequence (NCBI Reference 
               
               
                 Sequence: NM_001143678.1) 
               
               
                 ACATTCCTGACCTCTCCCTCCCCCTTTTCCCTCTTTCTTTCCTTCCTTCCTCCTCTTCCAAGTTCTGGGA 
               
               
                 TTTTTCAGCCTTGCTTGGTTTTGGCCAAAAGCACAAAAAAGGCGTTTTCGGAAGCGACCCGACCGTGCAC 
               
               
                 AAGGGCCATTTGTTTGTTTTGGGACTCGGGGCAGGAAATCTTGCCCGGCCTGAGTCACGGCGGCTCCTTC 
               
               
                 AAGGAAACGTCAGTGCTCGCCGGTCGCTCTCGTCTGCCGCGCGCCCCGCCGCCCGCTGCCCATGGGGGAG 
               
               
                 ATGCAGGGCGCGCTGGCCAGAGCCCGGCTCGAGTCCCTGCTGCGGCCCCGCCACAAAAAGAGGGCCGAGG 
               
               
                 CGCAGAAAAGGAGCGAGTCCTTCCTGCTGAGCGGACTGGCTTTCATGAAGCAGAGGAGGATGGGTCTGAA 
               
               
                 CGACTTTATTCAGAAGATTGCCAATAACTCCTATGCATGCAAACACCCTGAAGTTCAGTCCATCTTGAAG 
               
               
                 ATCTCCCAACCTCAGGAGCCTGAGCTTATGAATGCCAACCCTTCTCCTCCACCAAGTCCTTCTCAGCAAA 
               
               
                 TCAACCTTGGCCCGTCGTCCAATCCTCATGCTAAACCATCTGACTTTCACTTCTTGAAAGTGATCGGAAA 
               
               
                 GGGCAGTTTTGGAAAGGTTCTTCTAGCAAGACACAAGGCAGAAGAAGTGTTCTATGCAGTCAAAGTTTTA 
               
               
                 CAGAAGAAAGCAATCCTGAAAAAGAAAGAGGAGAAGCATATTATGTCGGAGCGGAATGTTCTGTTGAAGA 
               
               
                 ATGTGAAGCACCCTTTCCTGGTGGGCCTTCACTTCTCTTTCCAGACTGCTGACAAATTGTACTTTGTCCT 
               
               
                 AGACTACATTAATGGTGGAGAGTTGTTCTACCATCTCCAGAGGGAACGCTGCTTCCTGGAACCACGGGCT 
               
               
                 CGTTTCTATGCTGCTGAAATAGCCAGTGCCTTGGGCTACCTGCATTCACTGAACATCGTTTATAGAGACT 
               
               
                 TAAAACCAGAGAATATTTTGCTAGATTCACAGGGACACATTGTCCTTACTGACTTCGGACTCTGCAAGGA 
               
               
                 GAACATTGAACACAACAGCACAACATCCACCTTCTGTGGCACGCCGGAGTATCTCGCACCTGAGGTGCTT 
               
               
                 CATAAGCAGCCTTATGACAGGACTGTGGACTGGTGGTGCCTGGGAGCTGTCTTGTATGAGATGCTGTATG 
               
               
                 GCCTGCCGCCTTTTTATAGCCGAAACACAGCTGAAATGTACGACAACATTCTGAACAAGCCTCTCCAGCT 
               
               
                 GAAACCAAATATTACAAATTCCGCAAGACACCTCCTGGAGGGCCTCCTGCAGAAGGACAGGACAAAGCGG 
               
               
                 CTCGGGGCCAAGGATGACTTCATGGAGATTAAGAGTCATGTCTTCTTCTCCTTAATTAACTGGGATGATC 
               
               
                 TCATTAATAAGAAGATTACTCCCCCTTTTAACCCAAATGTGAGTGGGCCCAACGACCTACGGCACTTTGA 
               
               
                 CCCCGAGTTTACCGAAGAGCCTGTCCCCAACTCCATTGGCAAGTCCCCTGACAGCGTCCTCGTCACAGCC 
               
               
                 AGCGTCAAGGAAGCTGCCGAGGCTTTCCTAGGCTTTTCCTATGCGCCTCCCACGGACTCTTTCCTCTGAA 
               
               
                 CCCTGTTAGGGCTTGGTTTTAAAGGATTTTATGTGTGTTTCCGAATGTTTTAGTTAGCCTTTTGGTGGAG 
               
               
                 CCGCCAGCTGACAGGACATCTTACAAGAGAATTTGCACATCTCTGGAAGCTTAGCAATCTTATTGCACAC 
               
               
                 TGTTCGCTGGAAGCTTTTTGAAGAGCACATTCTCCTCAGTGAGCTCATGAGGTTTTCATTTTTATTCTTC 
               
               
                 CTTCCAACGTGGTGCTATCTCTGAAACGAGCGTTAGAGTGCCGCCTTAGACGGAGGCAGGAGTTTCGTTA 
               
               
                 GAAAGCGGACGCTGTTCTAAAAAAGGTCTCCTGCAGATCTGTCTGGGCTGTGATGACGAATATTATGAAA 
               
               
                 TGTGCCTTTTCTGAAGAGATTGTGTTAGCTCCAAAGCTTTTCCTATCGCAGTGTTTCAGTTCTTTATTTT 
               
               
                 CCCTTGTGGATATGCTGTGTGAACCGTCGTGTGAGTGTGGTATGCCTGATCACAGATGGATTTTGTTATA 
               
               
                 AGCATCAATGTGACACTTGCAGGACACTACAACGTGGGACATTGTTTGTTTCTTCCATATTTGGAAGATA 
               
               
                 AATTTATGTGTAGACTTTTTTGTAAGATACGGTTAATAACTAAAATTTATTGAAATGGTCTTGCAATGAC 
               
               
                 TCGTATTCAGATGCTTAAAGAAAGCATTGCTGCTACAAATATTTCTATTTTTAGAAAGGGTTTTTATGGA 
               
               
                 CCAATGCCCCAGTTGTCAGTCAGAGCCGTTGGTGTTTTTCATTGTTTAAAATGTCACCTGTAAAATGGGC 
               
               
                 ATTATTTATGTTTTTTTTTTTGCATTCCTGATAATTGTATGTATTGTATAAAGAACGTCTGTACATTGGG 
               
               
                 TTATAACACTAGTATATTTAAACTTACAGGCTTATTTGTAATGTAAACCACCATTTTAATGTACTGTAAT 
               
               
                 TAACATGGTTATAATACGTACAATCCTTCCCTCATCCCATCACACAACTTTTTTTGTGTGTGATAAACTG 
               
               
                 ATTTTGGTTTGCAATAAAACCTTGAAAAATATTTACATATAAAAAAAA 
               
               
                   
               
            
           
         
       
     
     EQUIVALENTS 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims: