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PET Clinics Jul 2024Neuroendocrine neoplasms (NEN) are rare tumors arising from neuroendocrine cells. NEN are ideally suited for a theragnostic approach due to their specific expression of... (Review)
Review
Neuroendocrine neoplasms (NEN) are rare tumors arising from neuroendocrine cells. NEN are ideally suited for a theragnostic approach due to their specific expression of somatostatin receptors (SSTR). SSTR imaging of NEN dates back to the 1980s, but has evolved recently due to the introduction of more sensitive SSTR PET radiotracers. SSTR PET is a primary imaging modality for identifying NEN and characterizing SSTR expression. SSTR PET is complementary to anatomic imaging for assessing tumor response to treatment. SSTR PET is mandated to determine eligibility for peptide receptor radionuclide therapy. Here, the role of imaging to aid management of NEN is reviewed.
Topics: Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Positron-Emission Tomography; Radiopharmaceuticals; Positron Emission Tomography Computed Tomography
PubMed: 38714399
DOI: 10.1016/j.cpet.2024.03.008 -
Archives of Medical Research Dec 2023Treatment strategies for NFPA include surgery, radiotherapy, medical treatment, or follow-up. The treatment of NFPAs with compressive symptoms is surgical. However, in... (Review)
Review
Treatment strategies for NFPA include surgery, radiotherapy, medical treatment, or follow-up. The treatment of NFPAs with compressive symptoms is surgical. However, in case of post-surgical tumor remnants, there may be treatment strategies that include observation and radiotherapy. Recently, medical treatment with cabergoline (CAB) has been recommended to contain and/or reduce the size of the tumor remnant. Based on the findings that many NFPAs show a dopamine receptor (DR) and somatostatin receptor (SR) expression, medical therapy with dopamine agonists (DAs) and somatostatin receptor ligands (SSRLs) has been tested as an alternative to prevent recurrence after surgery. The DAs have been the most extensively studied, showing some potential in terms of tumor shrinkage. SSRLs and other emerging medical options are much less studied. We will review and critically evaluate the current data on the medical therapy of NFPAs to elucidate their role in the management of this tumor type. In the case of actively growing remnants (more than 10% growth per year) and high-risk pituitary adenomas, treatment with CAB at a dose of 1.5-3.0 mg is indicated for tumor containment and/or reduction. In relation to combined chemotherapy with CAB, there is little information in the literature to support its use. In our experience, CAB treatment can be used after radiotherapy as an adjuvant treatment.
Topics: Humans; Pituitary Neoplasms; Receptors, Somatostatin; Adenoma; Receptors, Dopamine
PubMed: 37996269
DOI: 10.1016/j.arcmed.2023.102917 -
Islets Dec 2023Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated...
Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically encoded beta cell-specific GCaMP6f calcium reporter shows that somatostatin signaling alters beta cell calcium flux after physiologic glucose stimulation, an effect that depends on endogenous SSTR3 expression and the presence of intact primary cilia on beta cells. Comparative studies using SSTR isoform antagonists demonstrate a role for SSTR3 in mediating somatostatin regulation of insulin secretion in mouse islets. Our findings support a model in which ciliary SSTR3 mediates a distinct pathway of delta-to-beta cell regulatory crosstalk and may serve as a target for paracrine modulation.
Topics: Cilia; Glucose; Receptors, Somatostatin; Somatostatin; Animals; Mice
PubMed: 37660302
DOI: 10.1080/19382014.2023.2252855 -
Current Treatment Options in Oncology Mar 2021Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development... (Review)
Review
Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development strategies in this field. Somatostatin receptor type 2 (SSTR2) expression is the hallmark of well-differentiated neuroendocrine tumors (NETs). Somatostatin analogs and peptide receptor radionuclide therapy (PRRT) form the basis of anti-SSTR2 treatment onto new combination strategies, antibody-drug conjugates and bispecific antibodies. Classical pathways involved in NET development (PI3K-Akt-mTOR and antiangiogenics) are reviewed but new potential targets for NET treatment will be explored. Epigenetic drugs have shown clinical activity in monotherapy and preclinical combination strategies are more than attractive. Immunotherapy has shown opposite results in different NEN settings. Although the NOTCH pathway has been targeted with disappointing results, new strategies are being developed. Finally, after years of solid preclinical evidence on different genetically engineered oncolytic viruses, clinical trials for refractory NET patients are now ongoing.
Topics: Angiogenesis Inhibitors; Drug Development; Epigenesis, Genetic; Humans; Immunoconjugates; Immunotherapy; Neuroendocrine Tumors; Oncolytic Viruses; Protein Kinase Inhibitors; Radioisotopes; Receptors, Peptide; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 33786683
DOI: 10.1007/s11864-021-00834-3 -
European Journal of Cancer (Oxford,... Feb 2022Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on...
INTRODUCTION
Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy.
METHODS
We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763).
RESULTS
Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD).
CONCLUSIONS
This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.
Topics: Esthesioneuroblastoma, Olfactory; Humans; Nasal Cavity; Neuroblastoma; Nose Neoplasms; Positron-Emission Tomography; Radioisotopes; Radionuclide Imaging; Receptors, Somatostatin; Retrospective Studies
PubMed: 34980502
DOI: 10.1016/j.ejca.2021.09.046 -
International Journal of Molecular... Jun 2022Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of...
Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
Topics: Analgesics; Phagocytosis; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 35805885
DOI: 10.3390/ijms23136878 -
Frontiers in Endocrinology 2021Pancreatic neuroendocrine tumors (pNETs) are rare and part of the diverse family of neuroendocrine neoplasms (NENs). Somatostatin receptors (SSTRs), which are widely... (Review)
Review
Pancreatic neuroendocrine tumors (pNETs) are rare and part of the diverse family of neuroendocrine neoplasms (NENs). Somatostatin receptors (SSTRs), which are widely expressed in NENs, are G-protein coupled receptors that can be activated by somatostatins or its synthetic analogs. Therefore, SSTRs have been widely researched as a diagnostic marker and therapeutic target in pNETs. A large number of studies have demonstrated the clinical significance of SSTRs in pNETs. In this review, relevant literature has been appraised to summarize the most recent empirical evidence addressing the clinical significance of SSTRs in pNETs. Overall, these studies have shown that SSTRs have great value in the diagnosis, treatment, and prognostic prediction of pNETs; however, further research is still necessary.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 34093445
DOI: 10.3389/fendo.2021.679000 -
Surgery Jan 2020
Topics: Gallium Radioisotopes; Humans; Neuroendocrine Tumors; Receptors, Somatostatin
PubMed: 31629543
DOI: 10.1016/j.surg.2019.05.093 -
Journal of Neurosurgery Apr 2024The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the...
OBJECTIVE
The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs.
METHODS
A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion.
RESULTS
Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001).
CONCLUSIONS
Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.
Topics: Adult; Male; Female; Humans; Receptors, Somatostatin; Acromegaly; Insulin-Like Growth Factor I; Retrospective Studies; Adenoma; Somatostatin; Pituitary Neoplasms; RNA, Messenger
PubMed: 37856412
DOI: 10.3171/2023.7.JNS23858 -
APMIS : Acta Pathologica,... Apr 2023Insulinomas are rare pancreatic neuroendocrine tumours. Most patients can be cured with surgery, but patients with a metastatic disease show impaired survival. The aim...
Insulinomas are rare pancreatic neuroendocrine tumours. Most patients can be cured with surgery, but patients with a metastatic disease show impaired survival. The aim of this study was to evaluate somatostatin receptor (SSTR) 1-5 expression in insulinomas and to correlate the expression profile with clinicopathological variables and with patient outcome. This retrospective study involved 52 insulinoma patients. After histological re-evaluation, formalin-fixed paraffin-embedded tissue samples were processed into tissue microarrays and stained immunohistochemically with monoclonal SSTR1-5 antibodies. All the 52 tumours (49 non-metastatic, 3 metastatic) expressed at least one SSTR subtype. SSTR2 was expressed most frequently (71%), followed by SSTR3 (33%), SSTR1 (27%), SSTR5 (6%) and SSTR4 (0%). SSTR3 expression was associated with a larger tumour size (median diameter 19 mm vs. 13 mm, p = 0.043), and SSTR3 and SSTR5 expression were associated with impaired overall survival [HR 3.532 (95% CI 1.106-11,277), p = 0.033, and HR 6.805 (95% CI 1.364-33.955), p = 0.019 respectively]. Most insulinomas express SSTR2, which may be utilized in diagnostic imaging, and in planning individualized treatment strategies for insulinoma patients. Further studies are needed to clarify the association between SSTR profile and overall survival.
Topics: Humans; Receptors, Somatostatin; Insulinoma; Retrospective Studies; Gene Expression; Antibodies, Monoclonal; Pancreatic Neoplasms
PubMed: 36680557
DOI: 10.1111/apm.13297