Selective Glucocorticoid Receptor Research Articles

Glucocorticoid receptor-mediated oncogenic activity is dependent on breast cancer subtype

Breast cancer incidence has been steadily rising and is the leading cause of cancer death in women due to its high metastatic potential. Individual breast cancer subtypes are classified by both cell type of origin and receptor expression, namely estrogen, progesterone and human epidermal growth factor receptors (ER, PR and HER2). Recently, the importance and context-dependent role of glucocorticoid receptor (GR) expression in the natural history and prognosis of breast cancer subtypes have been uncovered. In ER-positive breast cancer, GR expression is associated with a better prognosis as a result of ER-GR crosstalk. GR appears to modulate ER-mediated gene expression resulting in decreased tumor cell proliferation and a more indolent cancer phenotype. In ER-negative breast cancer, including GR-positive triple-negative breast cancer (TNBC), GR expression enhances migration, chemotherapy resistance and cell survival. In invasive lobular carcinoma, GR function is relatively understudied, and more work is required to determine whether lobular subtypes behave similarly to their invasive ductal carcinoma counterparts. Importantly, understanding GR signaling in individual breast cancer subtypes has potential clinical implications because of the recent development of highly selective GR non-steroidal ligands, which represent a therapeutic approach for modulating GR activity systemically.

The effect of AZD9567 vs. prednisolone on glycaemic control in patients with type 2 diabetes mellitus: Results from a phase 2a clinical trial.

Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus. In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5mg daily (cohort 3). Treatment duration was 3days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring. A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001). AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone.

Vamorolone: revolutionizing Duchenne muscular dystrophy treatment

Duchenne muscular dystrophy (DMD) is a severe inherited neuromuscular disorder characterized by a dystrophin gene mutation, leading to progressive muscle weakness and structural degradation. Current management strategies focus on multidisciplinary approaches to mitigate symptoms and enhance quality of life. Conventional glucocorticoids present challenges due to their complex nature and severe side effects. Vamorolone, a first-in-class dissociative steroidal drug recently Food and Drug Administration (FDA) - approved, distinguishes itself through enduring anti-inflammatory effects with reduced safety concerns. Pharmacologically, Vamorolone's mechanism of action, differentiating it from traditional corticosteroids, involves selective glucocorticoid receptor (GR) modulation and mineralocorticoid receptor (MR) antagonism, offering improved safety and tolerability. Notably, its unique Δ9,11 modification prevents adverse receptor interactions, demonstrating superior safety in inhibiting inflammation across various cell types. This article explores Vamorolone's pharmacokinetics, drug interactions, and adverse effects, underscoring its well-tolerated profile with reversible hypothalamic-pituitary-adrenal axis suppression as a notable concern. Comparative studies against prednisone reveal Vamorolone's efficacy in improving muscle strength with minimal side effects, validated through the pivotal Phase IIb VISION-DMD study. Ultimately, Vamorolone has attained a breakthrough status in DMD treatment. Its endorsement by the FDA underscores Vamorolone as a transformative linchpin, heralding a new era in revolutionizing DMD care.

Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity

Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.

A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer.

The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.

Selective Modulation of the Human Glucocorticoid Receptor Compromises GR Chromatin Occupancy and Recruitment of p300/CBP and the Mediator Complex

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with the selective GR agonist and modulator dagrocorat compared to classic (ant)agonists, we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that dagrocorat and the antagonist RU486 both reduced GR interaction with CREB-binding protein/p300 and the mediator complex compared to the full GR agonist dexamethasone. Chromatin immunoprecipitation assays revealed that these changes in GR interactome were accompanied by reduced GR chromatin occupancy with dagrocorat and RU486. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses.

Potential Isoform Interactions Between GRs May Modulate Hippocampal Plasticity Under Different Stress Paradigms

This paper explores the potential interactions between glucocorticoid receptor (GR) isoforms in modulating hippocampal plasticity under varying stress conditions. The relationship between GR activity and hippocampal neurogenesis is complex, with evidence pointing to an inverted U-shaped association. We hypothesize that the hippocampus may differentially express GR-α and GR-β subtypes to fine-tune glucocorticoid signaling and neurogenesis. To test this, we propose utilizing CRISPR-Cas9-mediated genetic editing to generate mouse models with selective GR subtype expression in hippocampal dentate gyrus neurons. We would then expose these mice to controllable (wheel running) and uncontrollable (noise, social Defeat) stresses and quantify GR subtype expression using an advanced NanoBiT protein-interaction assay. The findings would provide insights into the nuanced roles of GR isoforms in mediating stress effects on neuroplasticity. This could inform potential interventions targeting GR balances for stress-related disorders.

Glucocorticoid receptor antagonist CORT113176 attenuates motor and neuropathological symptoms of Huntington's disease in R6/2 mice

Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD-related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell-type and brain region-specific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD-related symptoms, with the exception of the anti-epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option.

Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer.

Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

Synephrine and Its Derivative Compound A: Common and Specific Biological Effects.

This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRAs, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to their reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRAs. The review also provides insights into the safe pharmacological profile of synephrine.

Glucocorticoid Receptor Antagonism Improves Glucose Metabolism in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure. We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS. In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms. We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated Hsd11b1, which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues. We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice.

Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant Prostate Cancer.

In castration-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic prostate cancer patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs). For example, in the context of ARSi, we found that GR activation resulted in upregulation of protein kinase inhibitor beta (PKIB) mRNA and protein levels, leading to nuclear accumulation of the cAMP-dependent protein kinase A catalytic subunit (PKA-c). Increased PKA-c, in turn, is associated with increased cAMP response element-binding protein phosphorylation and activity. Furthermore, enzalutamide and SGRM combination therapy in mice bearing CRPC xenografts delayed CRPC progression compared with enzalutamide therapy alone, and reduced tumor PKIB mRNA expression. Supporting the clinical importance of GR/PKA signaling activation in CRPC, we found a significant enrichment of both cAMP pathway signaling-associated gene expression and high NR3C1 (GR) activity in patient-derived xenograft models and metastatic human CRPC samples. These findings suggest a novel mechanism linking CRPC-induced GR transcriptional activity with increased cAMP signaling in AR-antagonized CRPC. Furthermore, our findings suggest that GR-specific modulation in addition to AR antagonism may delay GR+ CRPC time to recurrence, at least in part, by inhibiting tumor cAMP/PKA pathways.

THU475 Ovarian Tumor-cell Glucocorticoid Receptor Activity Modulates Cytokine Secretion Promoting Recruitment And Activation of Immunosuppressive Cells Into The Tumor Microenvironment

Abstract Disclosure: M. Taya: None. E. LeBlanc: None. L. Bennett: None. S.D. Conzen: None. Elevated levels of immunosuppressive myeloid-derived suppressor cells (MDSCs) circulate in the peripheral blood or infiltrate both tumors and ascites in ovarian cancer patients, however the cause for this observed phenotype is unknown. MDSCs contribute to tumor immune tolerance primarily via inhibition of cytotoxic T-cells or by activation of immunosuppressive T-regulatory cells. We previously showed that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients. Additionally, using primary tumor data retrieved from the ovarian cancer TCGA dataset, we show high tumor GR expression is associated with significantly higher expression of Foxp3, a marker of immunosuppressive T-regulatory cells, as well as CD33, a marker of immunosuppressive myeloid cells, further suggesting an immunosuppressive phenotype in ovarian cancer patients. We thus hypothesize that tumor-intrinsic GR activation in ovarian cancer is associated with increased MDSC infiltration into the tumor microenvironment partly due to the modulation of tumor cell cytokine secretion. To determine whether tumor-cell GR activation modulates the cytokine secretome, we previously showed that GR activation in ovarian cancer cells upregulates secretion of immunomodulatory factors including G-CSF, TGFb and CXCL5. Moreover, co-treatment of cells with a selective GR modulator (SGRM) reverses this effect. Preliminary gene expression data indicate GR mediated cytokine secretion and signaling may involve post-transcriptional or post-translational mechanisms. Considering that elevated levels of these cytokines are necessary for the production and recruitment of MDSCs, these data highlight the relevance of this evident glucocorticoid receptor-cytokine circuit in ovarian cancer cells. Furthermore, we show that this tumor-cell cytokine secretome has the capacity to promote differentiation of MDSCs from precursor myeloid cells in healthy PBMCs. Importantly, measuring expression of activation markers such as Arginase-1 and NOS2 illustrated that these MDSCs are in their functional state. To our knowledge, this is the first evidence that a nuclear receptor in ovarian cancer tumor cells is actively driving MDSC differentiation. Finally, employing ovarian cancer xenograft models as well as a syngeneic ID8 tumor model, treatment with SGRMs demonstrated reduced levels of circulating MDSCs in the peripheral blood as well as tumor infiltrated MDSCs. Using neutralizing antibodies for cytokines, we will now identify key mechanisms, specifically, which targetable immunomodulatory factors are contributing to immune suppression. Based on the insight provided by these data, we propose to determine whether targeting ovarian tumor cell-intrinsic GR activation and resulting MDSC infiltration contributes to improved anti-tumor immune response. Presentation: Thursday, June 15, 2023

Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval

ObjectiveTo assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate–corrected QT interval (QTc). MethodsThree clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. ResultsAcross all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. ConclusionAt all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

THU035 Impact Of Surgery Or Medical Treatment With The Selective Glucocorticoid Receptor Modulator Relacorilant On Hypercoagulopathy In Patients With Cushing Syndrome

Abstract Disclosure: C. Simeoli: None. N. Di Paola: None. A. Stigliano: None. P. Lardo: None. T. Kearney: Other; Self; Corcept Therapeutics. E. Mezosi: Grant Recipient; Self; Corcept Therapeutics. E. Ghigo: None. R. Giordano: None. C.N. Mariash: Grant Recipient; Self; Corcept Therapeutics. D. Donegan: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.A. Feelders: Consulting Fee; Self; Recordati. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Recordati, HRA Pharma. A.L. Hand: Employee; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. R. Pivonello: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. In patients with Cushing syndrome (CS), hypercoagulability represents a significant concern, leading to an elevated risk for thrombotic events. Hypercoagulability persists for several months (mos) after curative surgery, and current CS treatment guidelines recommend anticoagulation therapy for up to 3 mos after surgery. In patients with Cushing disease, hemostatic parameters may even worsen after surgery, independent of surgical outcome, with improvements beginning about 3 mos after successful surgery (Casonato et al. Blood Coagul Fibrinolysis 1999). This transient worsening may be due to increased inflammation as cortisol levels, and hence cortisol’s anti-inflammatory effects, are reduced after successful surgery, leading to increased activity in the coagulation cascade, which normalizes over time. Here, we evaluate the impact of surgery or treatment with the selective glucocorticoid receptor modulator relacorilant (RELA) on the coagulation state in patients with CS, reporting findings from a retrospective, longitudinal, monocentric, surgical cohort study and an open-label phase 2 study of RELA (NCT02804750). In the surgical study, coagulation markers were assessed in 30 patients before curative surgery and in remission. In the RELA study, patients received either RELA 100-200 mg for 12 weeks or RELA 250-400 mg for 16 weeks; coagulation markers were assessed in 34 patients throughout the study. In the surgical study, baseline (BL) mean 24-h urinary free cortisol (UFC) was 615.6 mcg/day (by immunoassay; 2.1x upper limit of normal [ULN]); mean and median time to hemostasis assessment after remission were 6.2 and 6 mos, respectively. Significant mean changes from BL were observed in activated partial thromboplastin time (aPTT; +2.0 sec, P=0.031), factor VIII (fVIII; -24.2%, P=0.044), and von Willebrand factor (vWF; -20.6%, P=0.018), whereas platelet count was unchanged. In the RELA study, BL mean UFC was 211.9 mcg/day (by tandem mass spectrometry; 4.2x ULN). Similar to the surgical study, significant mean changes from BL to last observed visit were reported in aPTT (+1.5 sec, P=0.046), fVIII (-18.9%, P=0.022), and platelet count (-68.8*109/L, P&amp;lt;0.0001), while vWF was unchanged. Significant improvements in other coagulation factors, eg, fIX and fX, were seen in patients with abnormal values at BL. These studies showed that coagulation markers in patients with CS improve 6 mos after curative surgery, and that treatment with RELA may have similar effects after 3-4 mos. The previously observed transient increase in fVIII immediately after surgery was absent with RELA, where negative mean changes from BL were seen throughout the study. This is presumably due to the less abrupt reduction of cortisol activity with RELA compared to surgery. RELA’s effects on hypercoagulopathy support further investigation of preoperative use and in patients with CS who are not eligible for surgery. Presentation: Thursday, June 15, 2023

Withaferin A: A potential selective glucocorticoid receptor modulator with anti-inflammatory effect.

Glucocorticoids have been widely applied to various clinical treatment, however some serious side effects may occur during the treatment. It is widely known that glucocorticoids produce a marked effect through binding to glucocorticoid receptor (GR). As withaferin A can provide multiple health benefits, this work aims to confirm withaferin A as a potential selective GR modulator with anti-inflammatory effect. Fluorescence polarization assay confirmed that withaferin A could steadily bind to GR with an IC50 value of 203.80 ± 0.36 μM. Meanwhile, glucocorticoid receptor translocation of withaferin A was measured by nuclear fractionation assay. Dual luciferase reporter assay showed that withaferin A did not activate GR transcription. Furthermore, withaferin A decreased the GR-related protein expression with less side effects. The result of molecular docking showed that hydrogen-bonding and hydrophobic interactions contributed to the binding of withaferin A with GR. In addition, the GR-withaferin A complex maintained a stable binding throughout the dynamics simulation process. Enzyme-linked immunosorbent assay showed that withaferin A inhibited the production of cytokines, confirming its anti-inflammatory effect. These findings indicate that withaferin A is a potential selective GR modulator and this work may provide a research basis for developing dietary supplements and nutraceuticals against inflammation.

The glucocorticoid receptor modulator relacorilant reverses the immunosuppressive effects of cortisol

Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad transcriptional program that affects T-cell activation, pro-inflammatory cytokine secretion, apoptosis, and immune-cell trafficking. The degree to which endogenous cortisol blunts the anti-tumor immune response checkpoint inhibitors stimulate had not been assessed. We addressed this question using relacorilant, a selective GR modulator (SGRM) that competitively antagonizes the effects of cortisol activity. GR expression in human tumor and immune cells positively correlated with PD-L1 expression and tumor infiltration of Th2 and Treg cells, and negatively correlated with Th1-cell infiltration. In vitro, cortisol inhibited, and relacorilant restored, T-cell activation and pro-inflammatory cytokine secretion in human peripheral blood mononuclear cells. In the ovalbumin-expressing EG7 and MC38 immune-competent tumor models, relacorilant significantly improved anti-PD-1 antibody efficacy and showed favorable effects on antigen-specific T-cells and systemic TNFα and IL-10. These data characterize the broad immunosuppressive effects of endogenous cortisol and highlight the potential of combining an SGRM with an immune checkpoint inhibitor.

Impact of Surgery or Medical Treatment with the Selective Glucocorticoid Receptor Modulator Relacorilant on Hypercoagulopathy in Patients with Cushing Syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1403093: Absence of QT Prolongation Associated with Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Cushing Syndrome

QT prolongation is a significant concern for patients with Cushing syndrome (CS). Approximately 26% of men with CS present with QT prolongation, and the risk of cardiac arrhythmic events correlates with the extent of QT prolongation. All currently approved CS medications are associated with QT prolongation, posing a significant risk for the management of CS. Here, we evaluate the impact relacorilant, an investigational selective glucocorticoid receptor modulator, on QT prolongation in healthy volunteers and patients with CS. In a 3-part, single-center, first-in-human study (NCT03508635, “phase 1 study”), 103 healthy volunteers received single or multiple ascending doses of relacorilant (up to 500 mg QD) for up to 14 days; 24 received placebo. In a randomized, partial double-blind, crossover thorough QT study (NCT04795479, “TQT study”), the effect of multiple therapeutic (400 mg QD, n=25) and supra-therapeutic (800 mg QD, n=28) doses of relacorilant on cardiac repolarization was studied in healthy volunteers. A single dose of moxifloxacin (400 mg, n=28) was used as a positive control; 29 participants received placebo. In a single-arm, open-label phase 2 study (NCT02804750, “CS study”), 17 patients with CS received low-dose relacorilant (100–200 mg QD) for 12 weeks and 18 patients received high-dose relacorilant (250–400 mg QD) for 16 weeks. In all studies, ECG data were collected, and the heart rate-corrected QT interval using Fridericia’s formula (QTcF) was assessed. In the phase 1 study, relacorilant up to 500 mg daily did not adversely affect ECG parameters. An effect on placebo-corrected change from baseline QTcF (ΔΔQTcF) above 10 msec was excluded. In the TQT study, moxifloxacin control showed the expected QT prolongation, confirming assay sensitivity. Relacorilant had no adverse effects on ECG parameters and showed effects similar to placebo. Based on concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 msec was excluded within the full observed range of relacorilant plasma concentrations. These results constitute a negative TQT study. The CS study confirmed that these favorable findings also apply to patients with CS: Throughout the CS study, no significant changes in median QTcF were observed in either dose group. There is an unmet need for medications to treat CS that do not cause QT prolongation and possibly fatal arrhythmias. Based on the TQT study and supported by additional data in healthy volunteers and patients with CS, relacorilant did not show an association with QT prolongation.

Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Fortunately, recent advances in OC biology and the discovery of novel therapeutic targets have led to the development of novel therapeutic agents that may improve the outcome of OC patients. The glucocorticoid receptor (GR) is a ligand-dependent transcriptional factor known for its role in body stress reactions, energy homeostasis and immune regulation. Notably, evidence suggests that GR may play a relevant role in tumor progression and may affect treatment response. In cell culture models, administration of low levels of glucocorticoids (GCs) suppresses OC growth and metastasis. Conversely, high GR expression has been associated with poor prognostic features and long-term outcomes in patients with OC. Moreover, both preclinical and clinical data have shown that GR activation impairs the effectiveness of chemotherapy by inducing the apoptotic pathways and cell differentiation. In this narrative review, we summarize data related to the function and role of GR in OC. To this aim, we reorganized the controversial and fragmented data regarding GR activity in OC and herein describe its potential use as a prognostic and predictive biomarker. Moreover, we explored the interplay between GR and BRCA expression and reviewed the latest therapeutic strategies such as non-selective GR antagonists and selective GR modulators to enhance chemotherapy sensitivity, and to finally provide new treatment options in OC patients.