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Reviews in Endocrine & Metabolic... Sep 2021Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in... (Review)
Review
Both somatostatin (SST) and somatostatin receptors (SSTRs) are proteins with important functions in both physiological tissue and in tumors, particularly in neuroendocrine tumors (NETs). NETs are frequently characterized by high SSTRs expression levels. SST analogues (SSAs) that bind and activate SSTR have anti-proliferative and anti-secretory activity, thereby reducing both the growth as well as the hormonal symptoms of NETs. Moreover, the high expression levels of SSTR type-2 (SSTR2) in NETs is a powerful target for therapy with radiolabeled SSAs. Due to the important role of both SST and SSTRs, it is of great importance to elucidate the mechanisms involved in regulating their expression in NETs, as well as in other types of tumors. The field of epigenetics recently gained interest in NET research, highlighting the importance of this process in regulating the expression of gene and protein expression. In this review we will discuss the role of the epigenetic machinery in controlling the expression of both SSTRs and the neuropeptide SST. Particular attention will be given to the epigenetic regulation of these proteins in NETs, whereas the involvement of the epigenetic machinery in other types of cancer will be discussed as well. In addition, we will discuss the possibility to target enzymes involved in the epigenetic machinery to modify the expression of the SST-system, thereby possibly improving therapeutic options.
Topics: Epigenesis, Genetic; Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Somatostatin
PubMed: 33085037
DOI: 10.1007/s11154-020-09607-z -
PET Clinics Apr 2023Gastro-entero-pancreatic tumors comprise a group of heterogenous neoplasms, with medical imaging being paramount in the diagnosis, staging, and treatment planning of... (Review)
Review
Gastro-entero-pancreatic tumors comprise a group of heterogenous neoplasms, with medical imaging being paramount in the diagnosis, staging, and treatment planning of these tumors. Moreover, with the advent of newer radiopharmaceuticals, such as 68 Ga-labeled and 64 Cu-labeled somatostatin analogs (eg, 68 Ga-DOTATOC, 68 Ga-DOTATATE, 68 Ga-DOTANOC, and 64Cu-DOTATATE) that bind to the somatostatin receptor (SSTR), molecular imaging plays an increasing and critical role in the diagnosis, staging, and treatment planning of these neoplasms. Dual-tracer imaging with 18F-FDG PET/CT and SSTR agents may play a significant role in treatment planning and predicting patient outcomes in the setting of high-grade or poorly differentiated neuroendocrine tumors.
Topics: Humans; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Copper Radioisotopes; Positron-Emission Tomography; Pancreatic Neoplasms; Radiopharmaceuticals; Receptors, Somatostatin; Neuroendocrine Tumors; Organometallic Compounds
PubMed: 36707371
DOI: 10.1016/j.cpet.2022.11.007 -
Current Opinion in Endocrinology,... Feb 2020Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin... (Review)
Review
PURPOSE OF REVIEW
Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin receptors. Identification of these receptors has contributed to advancements in molecular and targeted radiotherapies.
RECENT FINDINGS
Molecular scans provide important diagnostic, staging, and prognostic data. Somatostatin-receptor imaging aids in selection of patients who are eligible for somatostatin-receptor-targeting therapies. Peptide receptor radionuclide therapy has recently demonstrated robust efficacy in a phase III study of progressive midgut NETs. Current studies are investigating novel receptor agonists and antagonists, new classes of radioactive isotopes, and radiosensitizing combination treatments.
SUMMARY
The sophistication of molecular imaging is improving and its importance is increasing as a diagnostic, predictive, and prognostic tool. Theranostics, the coupling of molecular imaging with receptor-targeted therapy, represents a novel approach to cancer treatment.
Topics: Humans; Molecular Imaging; Neoplasm Staging; Neuroendocrine Tumors; Prognosis; Radioisotopes; Receptors, Somatostatin
PubMed: 31789833
DOI: 10.1097/MED.0000000000000519 -
Reviews in Endocrine & Metabolic... Jun 2022Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike... (Review)
Review
Pasireotide, a novel multireceptor-targeted somatostatin receptor ligand (SRL) is characterized by a higher affinity to somatostatin receptor type 5 than type 2, unlike first-generation SRLs. Because of the broader binding profile, pasireotide has been suggested to have a greater clinical efficacy in acromegaly than first-generation SRLs and to be efficacious in Cushing's disease. The consequence of this binding profile is the increased blood glucose level in some patients. This results from the inhibition of both insulin secretion and the incretin effect and only a modest suppression of glucagon. A monthly intramuscular formulation of long-acting release pasireotide has been approved for both acromegaly and Cushing's disease treatment. This review presents data on the efficacy and safety of pasireotide treatment mostly in patients with acromegaly and Cushing's disease. Moreover, other possible therapeutic applications of pasireotide are mentioned.
Topics: Acromegaly; Humans; Ligands; Pituitary ACTH Hypersecretion; Receptors, Somatostatin; Somatostatin
PubMed: 35067849
DOI: 10.1007/s11154-022-09710-3 -
Theranostics 2021Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with...
Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with lutetium-177 is targeted to NET cells by binding to the somatostatin receptor subtype 2 (SST). During radioactive decay, DNA damage is induced, leading to NET cell death. Although the therapy proves to be effective, mortality rates remain high. To appropriately select more optimal treatment strategies, it is essential to first better understand the radiobiological responses of tumor cells to PRRT. We analyzed PRRT induced radiobiological responses in SST expressing cells and xenografted mice using SPECT/MRI scanning and histological and molecular analyses. We measured [Lu]Lu-DOTA-TATE uptake and performed analyses to visualize induction of DNA damage, cell death and other cellular characteristics. The highest accumulation of radioactivity was measured in the tumor and kidneys. PRRT induced DNA damage signaling and repair in a time-dependent manner. We observed intra-tumor heterogeneity of DNA damage and apoptosis, which was not attributed to proliferation or bioavailability. We found a strong correlation between high DNA damage levels and high SST expression. PRRT elicited a different therapeutic response between models with different SST expression levels. Heterogeneous SST expression levels were also confirmed in patient NETs. Heterogeneous SST expression levels within NETs cause differentially induced DNA damage levels, influence recurrent tumor phenotypes and impact the therapeutic response in different models and potentially in patients. Our results contribute to a better understanding of PRRT effects, which might impact future therapeutic outcome of NET patients.
Topics: Animals; Apoptosis; Cell Proliferation; Coordination Complexes; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Octreotide; Pancreatic Neoplasms; Radiopharmaceuticals; Receptors, Somatostatin; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33391488
DOI: 10.7150/thno.51215 -
Clinical Imaging 2019Somatostatin receptors (SSTR) are upregulated in the cells of origin that define numerous neuroendocrine neoplasms. PET imaging with Ga-DOTATATE allows specific... (Review)
Review
Somatostatin receptors (SSTR) are upregulated in the cells of origin that define numerous neuroendocrine neoplasms. PET imaging with Ga-DOTATATE allows specific targeting of SSTR2A, a single species of SSTR receptor, which is commonly overexpressed in a variety of gastroenteropancreatic neuroendocrine tumors, as well as pulmonary carcinoid and head and neck tumors. Due to more specific targeting of SSTR2 as well as lower radiation dose, shorter study length, ability to quantify uptake, and lower cost, Ga-DOTATATE has demonstrated superior imaging attributes when compared to In-pentetreotide. As with any novel imaging modality, dedicated training, increasing experience and staying up-to-date with scientific publications are required to provide optimal patient care. The purpose of this review is to summarize the current state of the art in SSTR-targeted molecular imaging and discuss ongoing and future potential diagnostic and therapeutic applications.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Molecular Imaging; Neuroendocrine Tumors; Organometallic Compounds; Positron-Emission Tomography; Receptors, Somatostatin
PubMed: 31121520
DOI: 10.1016/j.clinimag.2019.04.006 -
Progress in Molecular Biology and... 2023Somatostatin (SRIF) is a neuropeptide that acts as an important regulator of both endocrine and exocrine secretion and modulates neurotransmission in the central nervous... (Review)
Review
Somatostatin (SRIF) is a neuropeptide that acts as an important regulator of both endocrine and exocrine secretion and modulates neurotransmission in the central nervous system (CNS). SRIF also regulates cell proliferation in normal tissues and tumors. The physiological actions of SRIF are mediated by a family of five G protein-coupled receptors, called somatostatin receptor (SST) SST, SST, SST, SST, SST. These five receptors share similar molecular structure and signaling pathways but they display marked differences in their anatomical distribution, subcellular localization and intracellular trafficking. The SST subtypes are widely distributed in the CNS and peripheral nervous system, in many endocrine glands and tumors, particularly of neuroendocrine origin. In this review, we focus on the agonist-dependent internalization and recycling of the different SST subtypes in vivo in the CNS, peripheral organs and tumors. We also discuss the physiological, pathophysiological and potential therapeutic effects of the intracellular trafficking of SST subtypes.
Topics: Humans; Receptors, Somatostatin; Brain; Neoplasms
PubMed: 36813365
DOI: 10.1016/bs.pmbts.2022.09.004 -
Journal of Endocrinological... Nov 2020Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor... (Review)
Review
BACKGROUND
Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST and SST. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors.
METHODS
Critical revision of literature data correlating SST expression with patients' response to SRLs.
RESULTS
SST expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST expression, pasireotide can act throughout SST. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST expression observed in nearly 100% of cases, as well as to the balanced amount of SST. In corticotroph tumors, pasireotide mainly act via SST, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype.
CONCLUSIONS
The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.
Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 32557353
DOI: 10.1007/s40618-020-01335-0 -
Biochemical Society Transactions Feb 2021Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked... (Review)
Review
Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.
Topics: Animals; Cilia; Humans; Protein Interaction Domains and Motifs; Protein Sorting Signals; Protein Transport; Receptors, Serotonin; Receptors, Somatostatin
PubMed: 33599752
DOI: 10.1042/BST20191005 -
International Journal of Molecular... Apr 2021Somatostatin receptor subtype 4 (SST) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is...
Somatostatin receptor subtype 4 (SST) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST receptor expression and function between humans and mice, we generated an SST humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the and reporter gene construct driven by the regulatory elements were created. The vector was randomly inserted in -deficient mice. expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST humanized mouse line might enable us to investigate the differences of human and mouse SST receptor expression and function and assess the effects of SST receptor agonist drug candidates.
Topics: Animals; CA1 Region, Hippocampal; CA2 Region, Hippocampal; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Neurons; Receptors, Somatostatin
PubMed: 33916620
DOI: 10.3390/ijms22073758