Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant

Abstract

Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

Keywords: Cushing disease; adrenocorticotropic hormone; cortisol; ectopic ACTH syndrome; glucocorticoid; neuroendocrine tumor; relacorilant; somatostatin.

Conflict of interest statement

RP: Consultant: Ferring, Ipsen, Novartis, Pfizer, ViroPharma-Shire; Speaker: Novartis, ViroPharma-Shire; Research support: Corcept Therapeutics, Novartis, ViroPharma-Shire; Grant support: IBSA, Novartis, Pfizer, ViroPharma-Shire. PM: Consultant: Atlas, Alessa, EpiAxis, Rascal and AstraZeneca. MT: Consultant: HRA Pharma; Research support: Corcept Therapeutics. CS: Consultant: Ipsen, ViroPharma-Shire. UB: Consultant: Corcept Therapeutics; Employee: Sygnature Discovery, Ltd. AM: Employee: Corcept Therapeutics. The authors declare that the studies received funding from Corcept Therapeutics (Menlo Park, CA, USA). The funder had a role in study design, data collection and analysis. MA was employed by the company Corcept Therapeutics and, as an author of the manuscript and employee of Corcept Therapeutics, had a role in the study design, the decision to publish, the interpretation of clinical data, the revision of the manuscript, and approval of the final manuscript to submit. UB was employed by the company Sygnature Discovery Ltd. and, as an author of the manuscript and employee of Sygnature Discovery Ltd., supported by the funder, had a role in the preclinical data analysis and interpretation, decision to publish, revision of the manuscript, and approval of the final manuscript to submit. Open Access publication fees were paid by Corcept Therapeutics.

Copyright © 2022 Pivonello, Munster, Terzolo, Ferrigno, Simeoli, Puglisi, Bali and Moraitis.

Figures

Figure 1

The effects of glucocorticoid and glucocorticoid modulation with relacorilant on SSTR regulation. Created with BioRender.com.

Figure 2

Log2 fold change in SSTR2 mRNA in murine At-T20 cells upon treatment with increasing concentrations of relacorilant for 24 h in the presence of 100 nM dexamethasone. 0%, 2-fold, and 3-fold inhibition and 1.5-fold increase in levels are highlighted by dotted lines on the y-axis. Zero relative expression is in the absence of dexamethasone. Data points show average fold change compared to baseline and SD error bars. Data are technical replicates with an underlying n=1.

Figure 3

Imaging (A) and ACTH and cortisol levels (B) for case 1: a 46-year-old woman with an ectopic ACTH-secreting tumor (ectopic Cushing syndrome) treated with relacorilant for 16 weeks. (A) Octreotide scintigraphy. Increased uptake on post treatment imaging was consistent with increased expression of SSTR2s following treatment with relacorilant. (B) ACTH and cortisol levels before (baseline) and during relacorilant treatment. Normal laboratory ranges: ACTH, 6.0-50 pg/mL; serum cortisol, 4.6-20.6 µg/dL. To convert ACTH values from pg/mL to pmol/L, multiply by 0.22. To convert serum cortisol from µg/dL to nmol/L, multiply by 27.6. ACTH, adrenocorticotropic hormone.

Figure 4

ACTH and serum cortisol levels (A) and 68Ga-DOTATATE scans (B–E) in case 2: a 68-year-old man with a metastatic carcinoid NET treated with 7 cycles of relacorilant + nab-paclitaxel. (A) ACTH and cortisol levels before (baseline) and during relacorilant + nab-paclitaxel treatment. Patient received concomitant somatostatin analog. Normal laboratory ranges: ACTH, 6-50 pg/mL; morning serum cortisol, 4.6-20.6 µg/dL. To convert ACTH values from pg/mL to pmol/L, multiply by 0.22. To convert serum cortisol from µg/dL to nmol/L, multiply by 27.6. (B)68Ga-DOTATATE scan showed multiple lung and bone lesions at baseline before treatment with relacorilant. Repeat scan during treatment with relacorilant showed increased uptake without change in size of the lesions on CT. (C)68Ga DOTATATE scan showed multiple lung, liver, and bone lesions at baseline before treatment with relacorilant. Repeat scan during treatment with relacorilant showed increased uptake. (D)68Ga DOTATATE scan of L5 and left iliac bone lesions at baseline. Repeat scan during treatment with relacorilant showed increased uptake. (E) Compared with the 68Ga-DOTATATE scan before treatment with relacorilant, the repeat scan during relacorilant treatment showed increased uptake at the pituitary gland. ACTH, adrenocorticotropic hormone; NA, not available.

Figure 5

MRI of pituitary macroadenomas (A) and ACTH and cortisol levels (B) in case 3: a 50-year-old woman with Cushing disease treated with relacorilant for 12 weeks. (A) Coronal post contrast T1-weighted MRI obtained at diagnosis (left image) after administration of gadolinium showed a nodular lesion with reduced enhancement in the median and paramedian anterior part of the sellar region compatible with pituitary macroadenoma. It measured 10.01 × 6.29 × 4.91 mm. Pituitary MRI obtained (right image) within 12 weeks after the last dose of relacorilant showed a reduction in the size of the macroadenoma (8.04 × 5.70 × 3.65 mm). (B) ACTH and cortisol levels. Normal laboratory ranges: ACTH, 6.0-50 pg/mL; serum cortisol, 4.6-20.6 µg/dL. To convert ACTH values from pg/mL to pmol/L, multiply by 0.22. To convert serum cortisol from µg/dL to nmol/L, multiply by 27.6. ACTH, adrenocorticotropic hormone.

Figure 6

MRI of pituitary macroadenomas (A) and ACTH and cortisol levels (B) in case 4: a 43-year-old man with Cushing disease treated with relacorilant for 12 weeks. (A) Coronal post contrast T1-weighted MRI obtained at diagnosis (left image) after administration of gadolinium showed a pituitary macroadenoma measuring 22 × 25 × 26 mm with suprasellar extension, right displacement of the pituitary stalk, and invasion of the left cavernous sinus. The tumor was isointense to the gray matter and slightly inhomogeneous for the presence of cystic changes in its lower aspect. MRI of the hypophysis obtained within 12 weeks after the last dose of relacorilant (right image), after treatment with relacorilant, showed a reduction in the size of the macroadenoma (21 × 22 × 19 mm). (B) ACTH and cortisol levels. Normal laboratory ranges: ACTH, 6.0-50 pg/mL; serum cortisol, 4.6-20.6 µg/dL. To convert ACTH values from pg/mL to pmol/L, multiply by 0.22. To convert serum cortisol from µg/dL to nmol/L, multiply by 27.6. ACTH, adrenocorticotropic hormone.