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

Somatostatin receptor imaging (SRI) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Newer radiolabeled somatostatin analogs which can be used in positron emission tomography (PET) imaging, and which have a higher affinity for the somatostatin receptor, especially receptor subtype-2, have been developed. It would be desirable, however, if one radiolabeled analog became the new standard for PET imaging, because the current application of a multitude of analogs implies a fragmented knowledge on the interpretation of the images that are obtained in clinical practice. In our view, the most likely candidates for such a universal PET tracer for SRI are [68Ga-DOTA0,Tyr3]octreotate or [68Ga-DOTA0,Tyr3]octreotide. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all 111In-, 90Y-, or 177Lu-labeled somatostatin analogs that have been used for peptide receptor radionuclide therapy (PRRT). The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]octreotate. These data compare favorably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.

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

Frontiers in Endocrinology ◽

10.3389/fendo.2021.793262 ◽

2022 ◽

Vol 12 ◽

Author(s):

Rosario Pivonello ◽

Pamela N. Munster ◽

Massimo Terzolo ◽

Rosario Ferrigno ◽

Chiara Simeoli ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Neuroendocrine Tumors ◽

Tumor Size ◽

Somatostatin Receptor ◽

Pituitary Tumors ◽

Receptor Subtype ◽

Cushing Disease ◽

Ectopic Acth ◽

Somatostatin Receptor Subtype 2 ◽

Acth Secreting

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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Imaging of somatostatin receptor subtype 2 in advanced hepatocellular carcinoma by 68Ga-DOTATOC PET

Nuklearmedizin ◽

10.1055/s-0037-1621106 ◽

2009 ◽

Vol 48 (03) ◽

pp. N17-N18 ◽

Cited By ~ 1

Author(s):

M. Freesmeyer ◽

St. Schulz ◽

T. Knösel ◽

U. Settmacher

Keyword(s):

Hepatocellular Carcinoma ◽

Somatostatin Receptor ◽

Receptor Subtype ◽

Advanced Hepatocellular Carcinoma ◽

Somatostatin Receptor Subtype 2

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A new 68Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting

EJNMMI Research ◽

10.1186/s13550-020-00677-3 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Rosalba Mansi ◽

Karim Abid ◽

Guillaume P. Nicolas ◽

Luigi Del Pozzo ◽

Eric Grouzmann ◽

...

Keyword(s):

Amino Acids ◽

Somatostatin Receptor ◽

Somatostatin Analog ◽

Receptor Subtype ◽

Somatostatin Receptor Subtype 2

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Assessment of γ-H2AX and 53BP1 Foci in Peripheral Blood Lymphocytes to Predict Subclinical Hematotoxicity and Response in Somatostatin Receptor-Targeted Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers13071516 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1516

Author(s):

Thorsten Derlin ◽

Natalia Bogdanova ◽

Fiona Ohlendorf ◽

Dhanya Ramachandran ◽

Rudolf A. Werner ◽

...

Keyword(s):

Treatment Response ◽

Neuroendocrine Tumors ◽

Peripheral Blood ◽

Somatostatin Receptor ◽

Therapy Response ◽

Strand Break ◽

Peripheral Blood Lymphocytes ◽

Radioligand Therapy ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Blood Lymphocytes

Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

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