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Nature Structural & Molecular Biology Mar 2022Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors...
Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR subfamily, particularly SSTR2, are key drug targets for neuroendocrine neoplasms, with synthetic peptide agonists currently in clinical use. Here, we show the cryogenic-electron microscopy structures of active-state SSTR2 in complex with heterotrimeric G and either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition and receptor activation at SSTRs. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2 and substantial sequence divergence across subtypes in extracellular regions. Despite this complexity, we rationalize several known sources of SSTR subtype selectivity and identify an additional interaction for specific binding. These results provide valuable insights for structure-based drug discovery at SSTRs.
Topics: Ligands; Receptors, Somatostatin
PubMed: 35210615
DOI: 10.1038/s41594-022-00727-5 -
Future Oncology (London, England) Nov 2014Neuroendocrine tumors have shown rising incidence mainly due to higher clinical awareness and better diagnostic tools over the last 30 years. Functional imaging of... (Meta-Analysis)
Meta-Analysis Review
Neuroendocrine tumors have shown rising incidence mainly due to higher clinical awareness and better diagnostic tools over the last 30 years. Functional imaging of neuroendocrine tumors with PET tracers is an evolving field that is continuously refining the affinity of new tracers in the search for the perfect neuroendocrine tumor imaging tracer. (68)Ga-labeled tracers coupled to synthetic somatostatin analogs with differences in affinity for the five somatostatin receptor subtypes are now widely applied in Europe. Comparison of sensitivity between the most used tracers - (68)Ga-DOTA-Tyr3-octreotide, (68)Ga-DOTA-Tyr3-octreotate and (68)Ga-DOTA-l-Nal3-octreotide - shows little difference and expertise on the specific tracer used, and knowledge regarding physiological uptake might be more important than in vitro-proven differences in affinity. Using isotopes such as (18)F or (64)Cu might improve these PET tracers further.
Topics: Humans; Neuroendocrine Tumors; Positron-Emission Tomography; Radiometry; Radiopharmaceuticals; Receptors, Somatostatin; Reproducibility of Results; Sensitivity and Specificity
PubMed: 25471038
DOI: 10.2217/fon.14.139 -
The Journal of Clinical Endocrinology... Apr 2023
Topics: Humans; Acromegaly; Receptors, Somatostatin; Ligands; Octreotide; Somatostatin
PubMed: 36582134
DOI: 10.1210/clinem/dgac762 -
Neuroendocrinology 2022The overexpression of somatostatin receptor type 2 (SSTR2) is a unique characteristic of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), which establishes... (Comparative Study)
Comparative Study
Correlation and Comparison of Somatostatin Receptor Type 2 Immunohistochemical Scoring Systems with 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography Imaging in Gastroenteropancreatic Neuroendocrine Neoplasms.
INTRODUCTION
The overexpression of somatostatin receptor type 2 (SSTR2) is a unique characteristic of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), which establishes the basis for both diagnosis and therapy. The SSTR status can be evaluated by immunohistochemical staining (IHC) and 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) imaging. This study attempted to determine the relationship between IHC and 68Ga-DOTATATE PET/CT imaging and to explore the optimal cutoff value for SSTR IHC reading.
PATIENTS AND METHODS
A total of 100 GEP-NENs with SSTR PET/CT and pathological data were retrospectively analyzed, which consisted of neuroendocrine tumor (NET) G1 (n = 9), NET G2 (n = 64), NET G3 (n = 13), neuroendocrine carcinoma ( n = 10), and mixed neuroendocrine-non-NENs ( n = 4). SSTR2-IHC results were interpreted by 4 well-established semiquantitative scoring systems, including human epidermal growth factor receptor 2 (HER2) score, Volante score, H score, and immunoreactive score.
RESULTS
In the homogeneous SSTR2 expression group (accounting for 57% of all cases), the 4 scoring systems were highly concordant with each other (Kendall's Tau-b coefficient range: 0.80-0.96, p < 0.001) and also highly correlated with the 68Ga-DOTATATE PET/CT imaging results (Spearman's rank correlation coefficients: 0.71, 0.86, 0.80, and 0.71, p < 0.001). In the heterogeneous group (43%), the 4 scoring systems revealed a lower level of concordance (the Kendall Tau-b coefficient range: 0.40-0.75, p < 0.01), and the correlation with 68Ga-DOTATATE PET/CT imaging was also lower, albeit statistically significant (Spearman's rank correlation coefficients: 0.53, 0.38, 0.36, and 0.33, p < 0.05). Heterogeneous SSTR2 expression was mainly observed in the HER2 2+ cases, for which the combination with H score could help identify positive cases with increased sensitivity and specificity. The highest sensitivity and specificity of H scores in predicting the imaging results were achieved at 86.10 and 89.30% when defining the cutoff value as 160, indicating that 80% of the tumor cells were moderately positive or 55% were strongly positive.
CONCLUSIONS
SSTR2 IHC was found to predict 68Ga-DOTATATE PET/CT imaging accurately, especially in the homogeneous expression group. According to the positive 68Ga-DOTATATE PET/CT outcomes, 80% of the tumor cells moderately positive or 55% strongly positive was the cutoff values for SSTR2-IHC reading.
Topics: Humans; Neuroendocrine Tumors; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radionuclide Imaging; Receptors, Somatostatin; Retrospective Studies
PubMed: 34077939
DOI: 10.1159/000517530 -
Journal of the American College of... Jan 2023
Topics: Humans; Arteritis; Giant Cell Arteritis; Receptors, Somatostatin; Positron-Emission Tomography; Takayasu Arteritis; Fluorodeoxyglucose F18
PubMed: 36697135
DOI: 10.1016/j.jacc.2022.10.035 -
The Journal of Endocrinology Nov 2014Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is... (Review)
Review
Cushing's disease (CD) is characterized by an ACTH-producing anterior corticotrope pituitary adenoma. If hypothalamus-pituitary-adrenal (HPA) axis physiology is disrupted, ACTH secretion increases, which in turn stimulates adrenocortical steroidogenesis and cortisol production. Medical treatment plays an important role for patients with persistent disease after surgery, for those in whom surgery is not feasible, or while awaiting effects of radiation. Multiple drugs, with different mechanisms of action and variable efficacy and tolerability for controlling the deleterious effects of chronic glucocorticoid excess, are available. The molecular basis and clinical data for centrally acting drugs, adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are reviewed, as are potential novel molecules and future possible targets for CD treatment. Although progress has been made in the understanding of specific corticotrope adenoma receptor physiology and recent clinical studies have detected improved effects with a combined medical therapy approach, there is a clear need for a more efficacious and better-tolerated medical therapy for patients with CD. A better understanding of the molecular mechanisms in CD and of HPA axis physiology should advance the development of new drugs in the future.
Topics: Animals; Humans; Hypothalamo-Hypophyseal System; Ligands; Molecular Targeted Therapy; Pituitary ACTH Hypersecretion; Pituitary-Adrenal System; Receptors, Somatostatin; Signal Transduction; Somatostatin; Steroid Synthesis Inhibitors
PubMed: 25134660
DOI: 10.1530/JOE-14-0300 -
BMC Cancer Jul 2022Papillary and follicular thyroid carcinomas can be treated surgically and with radioiodine therapy, whereas therapeutic options for advanced stage IV medullary and for...
BACKGROUND
Papillary and follicular thyroid carcinomas can be treated surgically and with radioiodine therapy, whereas therapeutic options for advanced stage IV medullary and for anaplastic tumours are limited. Recently, somatostatin receptors (SSTs) and the chemokine receptor CXCR4 have been evaluated for the treatment of thyroid carcinomas, however, with contradictory results.
METHODS
The expression of the five SSTs and of CXCR4 was assessed in 90 samples from 56 patients with follicular, papillary, medullary, or anaplastic thyroid carcinoma by means of immunohistochemistry using well-characterised monoclonal antibodies. The stainings were evaluated using the Immunoreactivity Score (IRS) and correlated to clinical data. In order to further substantiate the immunohistochemistry results, in serial sections of a subset of the samples receptor expression was additionally examined at the mRNA level using qRT-PCR.
RESULTS
Overall, SST and CXCR4 protein expression was low in all four entities. In single cases, however, very high IRS values for SST2 and CXCR4 were observed. SST2 was the most frequently expressed receptor, found in 38% of cases, followed by SST5 and SST4, found in 14 and 9% of tumours, respectively. SST1 and SST3 could not be detected to any significant extent. CXCR4 was present in 12.5% of medullary and 25% of anaplastic carcinomas. Expression SST3, SST4, SST5 and CXCR4 was positively correlated with expression of the proliferation marker Ki-67. Additionally, a negative interrelationship between SST4 or SST5 expression and patient survival and a positive association between SST3 expression and tumour diameter were observed. qRT-PCR revealed a similar receptor expression pattern to that seen at the protein level. However, probably due to the low overall expression, no correlation was found for the SSTs or the CXCR4 between the IRS and the mRNA values.
CONCLUSIONS
SST- or CXCR4-based diagnostics or therapy in thyroid carcinomas should not be considered in general but may be feasible in single cases with high levels of expression of these receptors.
Topics: Antibodies, Monoclonal; Humans; Iodine Radioisotopes; RNA, Messenger; Receptors, CXCR4; Receptors, Somatostatin; Thyroid Neoplasms
PubMed: 35799158
DOI: 10.1186/s12885-022-09839-z -
The Journal of Endocrinology Mar 2024Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the... (Review)
Review
Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the thorax (lungs and thymus), thus representing a well-established target for medical treatment with SST ligands (SRLs). However, the response to SRLs is highly heterogeneous between tumors. Two main factors can contribute to this variability: (i) the differential SST expression among tumor types and (ii) the differential expression/modulation of the SST-related intracellular machinery. In this literature review, we provide an overview of available data on the variable expression of SSTs in pituitary tumors and NENs, together with the resulting clinical implications. Moreover, we aim to describe the complex intracellular machinery involved in SST signaling and trafficking. Particularly, we will focus on β-arrestins and describe their role in receptor internalization and recycling, as well as the various functions of these scaffold molecules in tumor pathogenesis and progression. This review highlights the interplay between membrane receptors and intracellular machinery, together with its role in determining the clinical behavior of the tumor and the response to treatment in patients with pituitary tumors or NENs.
Topics: Humans; Receptors, Somatostatin; Pituitary Neoplasms; Neuroendocrine Tumors
PubMed: 38224333
DOI: 10.1530/JOE-23-0298 -
Theranostics 2017Neuroendocrine tumors (NET) are often metastatic at the time of diagnosis. Metastatic well-differentiated (G1/G2) NET may display a wide range of behaviors, ranging from...
Neuroendocrine tumors (NET) are often metastatic at the time of diagnosis. Metastatic well-differentiated (G1/G2) NET may display a wide range of behaviors, ranging from indolent to aggressive, even within apparently homogeneous categories. Thus, selecting the optimal treatment strategy is a challenging task. Somatostatin receptor imaging (SRI) is the standard molecular imaging technique for well-differentiated NET. When performed with Ga-labeled somatostatin analogs (SRI-PET), it offers exquisite sensitivity for disease staging. SRI is also a prerequisite for using targeted radionuclide therapy (e.g. Lu-DOTATATE). 18F-FDG imaging has traditionally been reserved for staging poorly-differentiated G3 neuroendocrine carcinomas. However, recent data showed that FDG imaging has prognostic value in patients with well-differentiated NET: high uptake was associated with an increased risk of early progression while low uptake suggested an indolent tumor. In this issue of the Journal, Chan and colleagues propose a grading system where the results from the combined reading of SRI-PET and FDG-PET are reported as a single parameter, the "NETPET" score. While the scoring system still needs validation, it is clear that time has come to think about FDG and SRI in metastatic NET not as competitors but as complementary imaging modalities. Dual-tracer imaging can be viewed as a way to characterize disease phenotype in the whole-body. Moving from the prognostic value of dual-tracer imaging to a tool that allows for individualized management would require prospective trials. This editorial will argue that dual-tracer FDG-PET and SRI-PET might influence management of patients with well-differentiated metastatic NET and help selecting between different therapy options.
Topics: Fluorodeoxyglucose F18; Humans; Neuroendocrine Tumors; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prognosis; Prospective Studies; Receptors, Somatostatin
PubMed: 28435455
DOI: 10.7150/thno.19588 -
Advances in Therapy Oct 2023People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver...
INTRODUCTION
People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver or as self-injection via a proprietary or generic device. Injection device attributes that contribute to ease of use and storage, minimise preparation requirements, and reduce injection pain are associated with improved adherence and more favourable therapeutic outcomes. The aim of this study was to assess current opinion surrounding favourable SRL device attributes for people living with acromegaly and NETs as well as that of their caregivers.
METHODS
Participants (healthcare professionals [HCPs] and patients/non-HCP caregivers) from 11 countries were invited to answer survey questions related to their demographic, experience, and preferences as they relate to the real-world use of injectable SRL devices. Questions were developed based on review of available literature and meetings with a Scientific Committee.
RESULTS
Device attributes preferred by the patient/non-HCP caregiver group (n = 211) included confidence that the correct drug amount is delivered (76%), quick administration with minimal pain/discomfort (68%), and device safety (needle-safety and low risk of contamination; 53%). Device attributes preferred by HCPs (n = 52) were quick administration with minimal pain/discomfort (69%), correct use is easy to learn, confidence in handling the device (63%), and confidence that the correct drug amount is delivered (62%).
CONCLUSION
The results identified key features of injection devices for SRL therapy which merit consideration for optimal management and underscore the importance of patient partnership in treatment decisions.
Topics: Humans; Acromegaly; Somatostatin; Receptors, Somatostatin; Neuroendocrine Tumors; Ligands; Pain
PubMed: 37573277
DOI: 10.1007/s12325-023-02627-6