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Glioblastoma remains an incurable tumour (median survival: ~ 15 months) and little clinical progress has been made over the past decades. Therefore, identification of novel biomarkers and therapeutic targets is imperative. Targeting the somatostatin/cortistatin-system is considered a successful avenue for treating different tumour pathologies. Thus, we comprehensively characterized (clinically and molecularly) the expression of the somatostatin/cortistatin-system components [ligands and receptors (SSTRs)] using five cohorts of patients and tested the in-vitro therapeutic response of different SSTR-agonists and somatostatin analogs (SSAs) in primary patient-derived glioblastoma cells. A clear downregulation of the whole somatostatin/cortistatin-system (except for SSTR5) in glioblastoma vs . non-tumour brain samples was demonstrated, with high discriminatory capacity. Moreover, poor overall-survival and critical aggressiveness-parameters ( i.e., recurrence, IDH1 -wildtype and G-CIMP status, classical and mesenchymal GBM-subtypes, EGFR -amplification) were robustly associated with SSTR1/SSTR2 downregulation. Notably, octreotide, pasireotide, and SSTR1/2/5-agonists treatments significantly reduced cell-proliferation in primary patient-derived GBM-cells. Molecularly, antitumour effects of octreotide/pasireotide were exerted through key signalling-factors related to glioblastoma-aggressiveness ( i.e., CDKN1A-B/JAK-STAT/NF-κB/TGF-β-pathways). Altogether, this study demonstrated that somatostatin/cortistatin-system is drastically altered in GBM representing a useful prognostic tool, and that SSTR-modulators might represent a potential therapeutic strategy to treat specific subsets of patients with GBM.

Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH₂-CO-c(DCys-Phe-Tyr-DAgI⁸(Me,2-naphthoyl)-Lys-ThrPhe-Cys)-OH (sst₃-ODN-8) and a sst₂-selective antagonist (sst₂-ANT)], for labeling with$^{1ll/nat}ln$.$^{111/nat}ln-DOTA-sst_{3}-ODN-8$and$^{111/nat}lnDOTA-[4-NO_{2}-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH_{2}] (^{1ll/nat}lnDOTA-sst_{2}-ANT)$showed high sst₃- and sst₂-binding affinity, respectively. They did not trigger sst₃ or sst₂ internalization but prevented agonist-stimulated internalization.$^{111}ln-DOTA-sst_{3}ODN-8$and$^{111}1n-DOTA-sst_{2}-ANT$were injected intravenously into mice bearing sst₃- and sst₂-expressing tumors, and their biodistribution was monitored. In the sst₃-expressing tumors, strong accumulation of$^{111}ln-DOTA-sst_{3}-ODN-8$was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst₃-ODN-8 blocked uptake. As a control, the potent agonist$^{111}1n-DOTA-[1-Nal^{3}]-octreotide$, with strong sst₃-binding and internalization properties showed a much lower and shorter-lasting uptake in sst3-expressing tumors. Similarly,$^{111}1n-DOTA-sst_{2}-ANT$was injected into mice bearing sst₂expressing tumors. Tumor uptake was considerably higher than with the highly potent sst₂-selective agonist$^{111}1n-diethylenetriaminepentaacetic$acid-[Tyr⁳,Thr⁸]-octreotide ($^{111}1n-DTPA-TATE$). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst₃- or sst₂-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.

The somatostatin-secreting δ-cells comprise ~5% of the cells of the pancreatic islets. The δ-cells have complex morphology and might interact with many more islet cells than suggested by their low numbers. δ-Cells contain ATP-sensitive potassium channels, which open at low levels of glucose but close when glucose is elevated. This closure initiates membrane depolarization and electrical activity and increased somatostatin secretion. Factors released by neighbouring α-cells or β-cells amplify the glucose-induced effects on somatostatin secretion from δ-cells, which act locally within the islets as paracrine or autocrine inhibitors of insulin, glucagon and somatostatin secretion. The effects of somatostatin are mediated by activation of somatostatin receptors coupled to the inhibitory G protein, which culminates in suppression of the electrical activity and exocytosis in α-cells and β-cells. Somatostatin secretion is perturbed in animal models of diabetes mellitus, which might explain the loss of appropriate hypoglycaemia-induced glucagon secretion, a defect that could be mitigated by somatostatin receptor 2 antagonists. Somatostatin antagonists or agents that suppress somatostatin secretion have been proposed as an adjunct to insulin therapy. In this Review, we summarize the cell physiology of somatostatin secretion, what might go wrong in diabetes mellitus and the therapeutic potential of agents targeting somatostatin secretion or action.

Abstract Context Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)–dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. Objective Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. Methods Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical–pathological features of PPGLs. Results Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line “cold” somatostatin analogs 100% (n = 6, n = 3 SDHx). Conclusion SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor–based therapies in metastatic PPGLs.

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68 Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival. Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC.

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.

Somatostatin (SS) plays an important role in regulating food intake and following digestive functions of vertebrates mediated via somatostatin receptor (SSTR). However, the feedback regulation by which food intake regulate SS and SSTRs expression, and thereby their functions, remains poorly understood. Here, we cloned somatostatin genes ( pss1, pss2 and pss3 ) and somatostatin receptors genes ( sstr2a, sstr2b, sstr2c, sstr3a, sstr3b, sstr5a and sstr5b ) from tilapia, Oreochromis niloticus and conducted their tissue distribution. Phylogenetic analysis and genomic synteny maps revealed their high homology across the vertebrates and evolution history. Following, synthesized SS-14 and SS-28 were both confirmed to bind to SSTRs and mediated Erk1/2 or Akt phosphorylation in a dose-dependent manner and time-course effect in 293T cell line as well as tilapia primary hepatocytes. It was observed that the expression levels of SS family showed dynamic change during food intake. In the early stages of feeding, pss2 expressed in gastric epithelium was down-regulated by food intake, and the following low pH after feeding reversed to up-regulate the pss2 mRNA level. This down and up dynamic change hinted that the first down pss2 prompted food digesting and the next up pss2 inhibited digestion, but it might need further explore to prove. Compared with it, sstr3a expression levels in submucosa up-regulated after feeding but did not display dynamic change. Our results contribute to the understanding of how somatostatin family respond to food intake during different stages of feeding, which provides basis for subsequent study of their function in gastrointestine of tilapia.

G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G protein subtypes. Here we validate that in addition to the well-known G i/o pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the G q/11 pathway and show that smaller ligands preferentially activate the G i/o pathway. We further determined cryo-electron microscopy structures of the SSTR2‒G o and SSTR2‒G q complexes bound to octreotide and SST-14. Structural and functional analysis revealed that G protein selectivity of SSTRs is not only determined by structural elements in the receptor–G protein interface, but also by the conformation of the agonist-binding pocket. Accordingly, smaller ligands fail to stabilize a broader agonist-binding pocket of SSTRs that is required for efficient G q/11 coupling but not G i/o coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy. The combination of cryo-electron microscopy analysis with cell-signaling assays revealed promiscuous G i /G q coupling of somatostatin receptors and molecular mechanism of ligand-dependent selective G protein signaling

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst or sst but not sst or sst receptor agonists produced rapid and sustained inhibition of HPA axis. sst agonists selectively produced anxiolytic-like behaviors whereas both sst and sst agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sst KO mice and depressive-like behaviors observed in both sst KO and sst KO strains. Both hippocampal sst and sst receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.

The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA.