An immunohistochemical investigation of the expression of somatostatin receptor subtypes – should therapeutic trials be performed to determine the efficacy of somatostatin analogs in treating advanced thyroid malignances?

2015 ◽  
Vol 36 (07) ◽  
pp. 411-415
Author(s):  
H. Pisarek ◽  
M. Pawlikowski ◽  
M. Marchlewska ◽  
R. Minias ◽  
K. Winczyk
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Immunohistochemical Investigation ◽  
Therapeutic Trials ◽  
Somatostatin Receptor Subtypes

scholarly journals Evaluation of a New 177Lu-Labeled Somatostatin Analog for the Treatment of Tumors Expressing Somatostatin Receptor Subtypes 2 and 5

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4155
Author(s):  
Rosalba Mansi ◽  
Guillaume Pierre Nicolas ◽  
Luigi Del Pozzo ◽  
Karim Alexandre Abid ◽  
Eric Grouzmann ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Somatostatin Analog ◽  
Receptor Subtypes ◽  
In Vivo Evaluation ◽  
Somatostatin Receptor Subtypes ◽  
Lower Extent ◽  
Lower Background

Targeted radionuclide therapy of somatostatin receptor (SST)-expressing tumors is only partially addressed by the established somatostatin analogs having an affinity for the SST subtype 2 (SST2). Aiming to target a broader spectrum of tumors, we evaluated the bis-iodo-substituted somatostatin analog ST8950 ((4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2), having subnanomolar affinity for SST2 and SST5, labeled with [177Lu]Lu3+ via the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Human Embryonic Kidney (HEK) cells stably transfected with the human SST2 (HEK-SST2) and SST5 (HEK-SST5) were used for in vitro and in vivo evaluation on a dual SST2- and SST5-expressing xenografted mouse model. natLu-DOTA-ST8950 showed nanomolar affinity for both subtypes (IC50 (95% confidence interval): 0.37 (0.22–0.65) nM for SST2 and 3.4 (2.3–5.2) for SST5). The biodistribution of [177Lu]Lu-DOTA-ST8950 was influenced by the injected mass, with 100 pmol demonstrating lower background activity than 10 pmol. [177Lu]Lu-DOTA-ST8950 reached its maximal uptake on SST2- and SST5-tumors at 1 h p.i. (14.17 ± 1.78 and 1.78 ± 0.35%IA/g, respectively), remaining unchanged 4 h p.i., with a mean residence time of 8.6 and 0.79 h, respectively. Overall, [177Lu]Lu-DOTA-ST8950 targets SST2-, SST5-expressing tumors in vivo to a lower extent, and has an effective dose similar to clinically used radiolabeled somatostatin analogs. Its main drawbacks are the low uptake in SST5-tumors and the persistent kidney uptake.

Novel insights in somatostatin receptor physiology

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S3-S11 ◽  
Author(s):  
Giovanni Tulipano ◽  
Stefan Schulz
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Receptor Subtypes ◽  
Ligand Complex ◽  
Endosomal Sorting ◽  
Intracellular Vesicle ◽  
Molecular Events ◽  
Somatostatin Receptor Subtypes

The experimental data reviewed in the present paper deal with the molecular events underlying the agonist-dependent regulation of the distinct somatostatin receptor subtypes and may suggest important clues about the clinical use of somatostatin analogs with different pattern of receptor specificity for the in vivo targeting of tumoral somatostatin receptors. Somatostatin receptor subtypes are characterized by differential β-arrestin trafficking and endosomal sorting upon agonist binding due, at least in part, to the differences in their C-terminal tails. Moreover, the subcellular expression pattern of somatostatin receptor subtypes and their activity in response to agonist treatment are affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking. Different somatostatin analogs may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signaling or receptor endocytosis.

Prognostic role of somatostatin receptor subtypes in human prostate cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16120-e16120
Author(s):  
A. Gernone ◽  
V. Pagliarulo ◽  
S. Trabucco
Keyword(s):  
Prostate Cancer ◽  
Single Cells ◽  
Performance Status ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Neuroendocrine Differentiation ◽  
Patient Characteristics ◽  
Receptor Subtypes ◽  
Ecog Performance Status ◽  
Somatostatin Receptor Subtypes

e16120 Background: Neuroendocrine differentiation (NED) in prostate carcinoma (PC) is frequently detected by immunohistochemistry as single cells in conventional adenocarcinoma. NED of PC correlates with poor prognosis and tumor progression during androgen-deprivation therapy. The aim of our study was to correlate the expression of somatostatin receptor (SSTR) 1, 2, 3, 4, 5 subtypes in primary PC with NED pattern and Overall Survival (OS). Methods. PC tissues were reviewed from 100 pts who had undergone biopsy or radical prostatectomy for previously untreated advanced or metastatic PC from 2002 to 2007. 24 samples expressed hystologically chromogranin A (CgA), a marker of NED expression. Patient characteristics included: median age 68 years (range 45–83), median baseline PSA: 70 ng/ml (range 0.3–200), median ECOG Performance Status: 1 (range 0–2), Gleason score ≥ 7, medium serum level of CgA was 56.2 nmol/L (range 0.5–120). Results: The expression of SSTR subtypes (1, 2, 3, 4, 5) were investigated and our data identified four histological features. SSTR1 was expressed in 4/24 samples, SSTR 5 was detected in 2/24 samples, both SSTR1 and SSTR5 were found in 6/24 samples. OS at last follow up on July 2008 was 60%. SSTR 1–5 were undetectable in 12/24 pts with more aggressive clinical course and the OS was < 10%. The PSA and CgA levels were not correlated with clinical outcome. SSTR subtypes 2, 3 an 4 were not expressed in all 24 samples. Conclusions: SSTRs expression significantly correlated with OS. The absence of SSTR 1 and 5 in more aggressive disease could represent a growth advantage in NED prostate cancer. SSTRs and somatostatin analogs are potential targets for prostate cancer treatment. No significant financial relationships to disclose.

scholarly journals Expression and Functional Analysis of Dopamine Receptor Subtype 2 and Somatostatin Receptor Subtypes in Canine Cushing’s Disease

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4357-4366 ◽  
Author(s):  
C. de Bruin ◽  
J. M. Hanson ◽  
B. P. Meij ◽  
H. S. Kooistra ◽  
A. M. Waaijers ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Dopamine Receptor ◽  
Anterior Pituitary ◽  
Dopamine Agonists ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Somatostatin Receptor Subtypes ◽  
Corticotroph Adenomas

Cushing’s disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.

scholarly journals SAT-305 Veldoreotide (COR005) Mechanisms of Action Studies: Comparison to Octreotide and Pasireotide

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Pooja Dasgupta ◽  
Stefan Schulz
Keyword(s):  
G Protein ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Hek293 Cells ◽  
Receptor Subtypes ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Response Curves ◽  
Somatostatin Receptor Subtypes ◽  
First Choice

Abstract Stable somatostatin analogs (SSAs) are the first choice for medical treatment of pituitary adenomas and other neuroendocrine tumors. The somatostatin analogs octreotide, pasireotide, and veldoreotide primarily have been characterized according to their binding profiles. However, their ability to activate individual somatostatin receptor subtypes (SSTs) has not been directly assessed so far. In this study, we assessed G-protein signaling in human embryonic kidney (HEK293) cells stably expressing G protein-coupled inwardly rectifying potassium (GIRK) channels and SSTs using a novel fluorescence-based membrane potential assay. Dose-response curves obtained for veldoreotide revealed high potency and efficacy in cells expressing SST2, SST4, and SST5. Veldoreotide also inhibited proliferation and chromogranin A secretion in SST4-transfected BON-1 cells. In addition, we assessed G-protein signaling in primary pituitary cultures from SST2 and SST5 knockout mice. Our results show that octreotide mediates its effects selectively via the SST2 receptor. Conversely, pasireotide mediates its effects selectively via the SST5 receptor. In contrast, veldoreotide can activate both SST2 and SST5 receptors under otherwise identical conditions. Thus, veldoreotide is a unique SSA with full agonistic activity at the SST2, SST4, and SST5 receptors.

scholarly journals Immunohistochemical Expression of Somatostatin Receptor Subtypes in a Panel of Neuroendocrine Neoplasias

2019 ◽  
Vol 67 (10) ◽  
pp. 735-743 ◽  
Author(s):  
Satu M. Remes ◽  
Helena L. Leijon ◽  
Tiina J. Vesterinen ◽  
Johanna T. Arola ◽  
Caj H. Haglund
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Somatostatin Analogs ◽  
Membrane Receptors ◽  
Receptor Subtypes ◽  
Receptor Imaging ◽  
Primary Tumors ◽  
Somatostatin Receptor Subtypes ◽  
Negative Controls ◽  
G Protein Coupled

Neuroendocrine neoplasias (NENs) are known to express somatostatin receptors (SSTRs) 1–5, which are G-protein-coupled cell membrane receptors. Somatostatin receptor imaging and therapy utilizes the SSTR expression. Synthetic somatostatin analogs with radioligands are used to detect primary tumors, metastases, and recurrent disease. Receptor analogs are also used for treating NENs. Furthermore, commercially available SSTR antibodies can be used for the immunohistochemical (IHC) detection of SSTRs. We investigated different SSTR antibody clones applying diverse IHC protocol settings to identify reliable clones and feasible protocols for NENs. A tissue microarray including NENs from 12 different primary sites were stained. Only UMB clones were able to localize SSTR on the cell membranes of NENs. SSTR2 (UMB1) emerged as the most common subtype followed by SSTR5 (UMB4) and SSTR1 (UMB7). SSTR3 (UMB5) expression was mainly cytoplasmic. Yet, SSTR4 expression was weak and located primarily in the cytoplasm. Thus, appropriate IHC protocols, including proper positive and negative controls, represent requirements for high-quality NEN diagnostics and for planning personalized therapy.

scholarly journals Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro

2009 ◽  
Vol 94 (2) ◽  
pp. 654-661 ◽  
Author(s):  
Sarah Lesche ◽  
Diana Lehmann ◽  
Falko Nagel ◽  
Herbert A. Schmid ◽  
Stefan Schulz
Keyword(s):  
Plasma Membrane ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Activation ◽  
Receptor Internalization ◽  
Receptor Subtypes ◽  
Human Embryonic Kidney Cells ◽  
Somatostatin Receptor Subtypes ◽  
Term Administration

Abstract Objective: The clinically used somatostatin analogs, octreotide and lanreotide, act primarily by binding to somatostatin receptor 2 (sst2). In contrast, the novel multireceptor ligand pasireotide (SOM230) binds with high affinity to somatostatin receptor subtypes sst1, sst2, sst3, and sst5. SOM230 is currently under clinical evaluation for treatment of acromegaly, Cushing’s disease, and octreotide-resistant carcinoid tumors. However, the effects of SOM230 on internalization and postendosomal sorting of individual human somatostatin receptor subtypes have not been determined so far. Results: Here we show that SOM230 was less potent than octreotide in inducing internalization and signaling of sst2 receptors expressed in human embryonic kidney cells. In contrast, SOM230 was more potent than octreotide in inducing internalization and signaling of sst3 and sst5 receptors. Both SOM230 and octreotide stimulated a rapid down-regulation of sst3 but not of sst2 or sst5 receptors. SOM230 and octreotide profoundly differed in their patterns of sst2-stimulated β-arrestin mobilization. Whereas octreotide-mediated receptor activation led to the formation of stable complexes facilitating the internalization of sst2 and β-arrestin-2 into the same endocytic vesicles, SOM230-mediated receptor activation led to the formation of unstable complexes that dissociated at or near the plasma membrane. Consequently, sst2 receptors recycled rapidly to the plasma membrane after endocytosis in SOM230-treated cells, but not in octreotide-treated cells. Conclusion: We show that SOM230 modulates somatostatin receptor trafficking in a manner clearly distinct from octreotide and somatostatin. These findings may provide an explanation for the differential regulation of somatostatin receptor responsiveness during long-term administration of stable somatostatin analogs.

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