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

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).

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X-linked acrogigantism syndrome: clinical profile and therapeutic responses

Endocrine Related Cancer ◽

10.1530/erc-15-0038 ◽

2015 ◽

Vol 22 (3) ◽

pp. 353-367 ◽

Cited By ~ 88

Author(s):

Albert Beckers ◽

Maya Beth Lodish ◽

Giampaolo Trivellin ◽

Liliya Rostomyan ◽

Misu Lee ◽

...

Keyword(s):

Anterior Pituitary ◽

Tumor Tissue ◽

Clinical Phenotype ◽

Somatostatin Receptor ◽

Somatostatin Analogs ◽

Pituitary Tumors ◽

Receptor Subtype ◽

Sporadic Cases ◽

Somatostatin Receptor Subtype 2 ◽

Median Height

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the geneGPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

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Internalized Somatostatin Receptor Subtype 2 in Neuroendocrine Tumors of Octreotide-Treated Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2487 ◽

2010 ◽

Vol 95 (5) ◽

pp. 2343-2350 ◽

Cited By ~ 40

Author(s):

Jean Claude Reubi ◽

Beatrice Waser ◽

Renzo Cescato ◽

Beat Gloor ◽

Christoph Stettler ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Autoradiography ◽

Receptor Expression ◽

Receptor Subtype ◽

High Dose ◽

Somatostatin Receptor Subtype 2 ◽

In Vitro Receptor Autoradiography

Abstract Context: Somatostatin receptor subtype 2 (sst2) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst2 tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst2. Patients and Methods: In the present study, we evaluated whether sst2 expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst2 immunohistochemistry was performed in all samples with three different sst2 antibodies (R2-88, UMB-1, and SS-800). Sst2 receptor expression was confirmed by immunoblotting and in vitro receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst2, and patients with a low dose of octreotide had a variable ratio of internalized vs. membranous sst2, whereas untreated patients had exclusively membranous sst2. The internalized sst2 receptor corresponded to a single sst2 band in immunoblots and to sst2 receptors in in vitro receptor autoradiography. Although generally found in endosome-like structures, internalized sst2 receptors were also identified to a small extent in lysosomes, as seen in colocalization experiments. Conclusion: It is the first evidence showing that sst2 receptors can be internalized in sst2-expressing neuroendocrine tumors in patients under octreotide therapy, providing clues about sst2 receptor biology and trafficking dynamics in patients.

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MicroRNAs Differentially Expressed in ACTH-Secreting Pituitary Tumors

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-1451 ◽

2009 ◽

Vol 94 (1) ◽

pp. 320-323 ◽

Cited By ~ 112

Author(s):

Fernando Colbari Amaral ◽

Natalia Torres ◽

Fabiano Saggioro ◽

Luciano Neder ◽

Hélio Rubens Machado ◽

...

Keyword(s):

Mirna Expression ◽

Tumor Size ◽

Target Genes ◽

Pituitary Tumors ◽

Mirna Expression Profile ◽

Fragile Sites ◽

Cushing Disease ◽

Small Noncoding Rnas ◽

Mirna Genes ◽

Acth Secreting

Abstract Context: MicroRNAs (miRNAs) are small noncoding RNAs, functioning as antisense regulators of gene expression by targeting mRNA and contributing to cancer development and progression. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites of the genome. Objective: The aim of the study was to analyze the differential expression of let-7a, miR-15a, miR-16, miR-21, miR-141, miR-143, miR-145, and miR-150 in corticotropinomas and normal pituitary tissue and verify whether their profile of expression correlates with tumor size or remission after treatment. Material and Methods: ACTH-secreting pituitary tumor samples were obtained during transphenoidal surgery from patients with Cushing disease and normal pituitary tissues from autopsies. The relative expression of miRNAs was measured by real-time PCR using RNU44 and RNU49 as endogenous controls. Relative quantification of miRNA expression was calculated using the 2−ΔΔCt method. Results: We found underexpression of miR-145 (2.0-fold; P = 0.04), miR-21 (2.4-fold; P = 0.004), miR-141 (2.6-fold; P = 0.02), let-7a (3.3-fold; P = 0.003), miR-150 (3.8-fold; P = 0.04), miR-15a (4.5-fold; P = 0.03), miR-16 (5.0-fold; P = 0.004), and miR-143 (6.4-fold; P = 0.004) in ACTH-secreting pituitary tumors when compared to normal pituitary tissues. There were no differences between miRNA expression and tumor size as well as miRNA expression and ratio of remission after surgery, except in patients presenting lower miR-141 expression who showed a better chance of remission. Conclusion: Our results support the possibility that altered miRNA expression profile might be involved in corticotrophic tumorigenesis. However, the lack of knowledge about miRNA target genes postpones full understanding of the biological functions of down-regulated or up-regulated miRNAs in corticotropinomas.

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Cushing Disease Due to Ectopic Pituitary Adenoma.

10.46940/gjsst.01.1006 ◽

2019 ◽

pp. 1-5

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Adrenocorticotropic Hormone ◽

Pituitary Tumors ◽

Pituitary Stalk ◽

Cushing Disease ◽

Ectopic Acth ◽

Common Cause ◽

Ectopic Pituitary Adenoma ◽

Acth Secreting

Abstract Adrenocorticotropic hormone (ACTH) - secreting pituitary adenomas are the most common cause of Cushing disease. A pituitary adenoma is rarely ectopic and suprasellar dependent (ectopic) ACTH -secreting pituitary tumors are extremely rare, with few cases described in the literature. Therefore, this study aimed to report the case of a patient with a diagnosis of Cushing disease because of a suprasellar ACTH-secreting tumor attached to the pituitary stalk, requiring a craniotomy.

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Prevalence of somatostatin receptor subtype 2 in somatostatin receptor positive, gastroenteropancreatic neuroendocrine tumors

Gastroenterology ◽

10.1016/0016-5085(95)26454-x ◽

1995 ◽

Vol 108 (4) ◽

pp. A535

Author(s):

H. Scherübl ◽

M. John ◽

W. Meyerhof ◽

D. Richter ◽

B. Waser ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Subtype ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Somatostatin Receptor Subtype 2

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Ectopic Adrenocorticotropic Hormone–Secreting Pituitary Adenomas: An Underestimated Entity

Neurosurgery ◽

10.1227/neu.0000000000001319 ◽

2017 ◽

Vol 80 (4) ◽

pp. 525-533 ◽

Cited By ~ 8

Author(s):

Ulrich J. Knappe ◽

Christian Jaspers ◽

Desirée Buschsieweke ◽

Wolf-Dieter Reinbold ◽

Ali Alomari ◽

...

Keyword(s):

Computed Tomography ◽

Positron Emission Tomography ◽

Pituitary Adenomas ◽

Adrenocorticotropic Hormone ◽

Somatostatin Receptor ◽

Emission Tomography ◽

Cushing Disease ◽

Ectopic Acth ◽

Positron Emission ◽

Acth Secreting

AbstractBACKGROUND: The diagnosis of Cushing disease is based on endocrinological pa-rameters, with no single test being specific. In some patients, dynamic thin-slice sellar magnetic resonance imaging fails to detect a pituitary tumor.OBJECTIVE: The purpose of this study is to investigate the role of ectopic pituitary adenoma in this situation.METHODS: In a retrospective chart review, 5 patients (6%) with ectopic adenomas were identified in 83 consecutive patients undergoing transsphenoidal surgery for adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas by 1 surgeon.RESULTS: In all 5 patients (all female, 32-41 years of age), an exclusively extrasellar ACTH-secreting adenoma was excised. Three adenomas were located in the cavernous sinus, 1 in the sphenoid sinus, and 1 in the ethmoidal cells. Histologically, none of the tumors showed signs of aggressiveness. Three of the 5 adenomas specifically expressed somatostatin receptor 5. In 4 patients with Cushing disease, postoperative remission was obtained, with 1 recurrence after 14 months. In the patient with Nelson syndrome, ACTH decreased from >800 to <80 pg/mL. Three patients underwent previous surgery elsewhere, including 1 hypophysectomy. In this case, the ectopic adenoma (positive for somatostatin receptor 5) in the ethmoidal cells turned out to be positive on gallium 68 DOTATATE positron emission tomography/computed tomography.CONCLUSION: The incidence of primarily ectopic ACTH-secreting adenomas in this series was 6%. In cases of negative MRI findings, an ectopic ACTH-secreting adenoma should be taken into account. 68Ga DOTATATE positron emission tomography/computed tomography may identify ectopic pituitary adenomas. Hypophysectomy should always be avoided in primary surgery for CD.

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