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Journal of Nuclear Medicine : Official... Oct 2021A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals...
A new era of precision diagnostics and therapy for patients with neuroendocrine neoplasms began with the approval of somatostatin receptor (SSTR) radiopharmaceuticals for PET imaging followed by peptide receptor radionuclide therapy (PRRT). With the transition from SSTR-based γ-scintigraphy to PET, the higher sensitivity of the latter raised questions regarding the direct application of the planar scintigraphy-based Krenning score for PRRT eligibility. Also, to date, the role of SSTR PET in response assessment and predicting outcome remains under evaluation. In this comprehensive review article, we discuss the current role of SSTR PET in all aspects of neuroendocrine neoplasms, including its relation to conventional imaging, selection of patients for PRRT, and the current understanding of SSTR PET-based response assessment. We also provide a standardized reporting template for SSTR PET with a brief discussion.
Topics: Neuroendocrine Tumors; Positron-Emission Tomography; Precision Medicine; Receptors, Somatostatin
PubMed: 34301785
DOI: 10.2967/jnumed.120.251512 -
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 -
PET Clinics Apr 2023Recently, advancement of somatostatin receptor (SSTR) imaging and theragnostic approach using peptide receptor radionuclide therapy (PRRT) have changed the paradigm of... (Review)
Review
Recently, advancement of somatostatin receptor (SSTR) imaging and theragnostic approach using peptide receptor radionuclide therapy (PRRT) have changed the paradigm of diagnosis and management of neuroendocrine tumor. 68Ga-DOTATATE PET/CT can diagnose the lung carcinoids with high SSTR expression. With combination of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT, tumor heterogeneity of lung carcinoid can be identified, which may guide optimal patient selection for PRRT. PRRT may be an effective and safe treatment of advanced lung carcinoids during progression with first-line somatostatin analog therapy. This review provides updates on the diagnosis and management of lung carcinoids, focusing on SSTR imaging and PRRT.
Topics: Humans; Receptors, Somatostatin; Positron Emission Tomography Computed Tomography; Organometallic Compounds; Lung Neoplasms; Positron-Emission Tomography; Neuroendocrine Tumors; Carcinoid Tumor; Radioisotopes; Lung
PubMed: 36585338
DOI: 10.1016/j.cpet.2022.11.005 -
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 -
Journal of Peptide Science : An... Dec 2021Somatostatin analogues play an important role in the therapy of neuroendocrine tumors by binding to somatostatin receptors on the surface of cancer cells. In this work,...
Somatostatin analogues play an important role in the therapy of neuroendocrine tumors by binding to somatostatin receptors on the surface of cancer cells. In this work, we analyze the receptor-binding affinity and in vitro stability of a novel ultra-short somatostatin analogue Thz-Phe-D-Trp-Lys-Thr-DOTA (DOTA-P4). This conjugate is successfully radiolabeled with Sc, Y, Eu, and Bi, characterized and validated by thin layer and high-performance liquid chromatography. The optimum conditions for M-DOTA-P4 labeling are found. In vitro stability studies are performed in saline, in the presence of serum proteins, and with biologically relevant metal cations. All complexes demonstrate no cation release in vitro within 4-24 h. The conformations of DOTA-conjugates are studied by circular dichroism spectroscopy. The circular dichroism spectra of DOTA-P4 conjugates show a negative peak at 225 nm, which may correspond to the required β-sheet conformation. The binding to somatostatin receptors of types 2 and 5 is performed with the IMR-32 cells at 4°C, with non-specific binding representing 26% of the total binding. A two-line approximation of the Scatchard plot results in the apparent dissociation constants of 0.10 and 2.25 nM. It is shown that the chelator position with respect to the amino acid sequence significantly affects the labeling conditions with cations of different ionic radii. For the first time, the binding of a linear type ultra-short peptide conjugate with DOTA to somatostatin receptors is demonstrated. The obtained results are promising for experiments with DOTA-P4 in vivo in mice with inoculated tumors.
Topics: Animals; Heterocyclic Compounds, 1-Ring; Mice; Peptides; Receptors, Somatostatin; Somatostatin
PubMed: 34291534
DOI: 10.1002/psc.3361 -
Hellenic Journal of Nuclear Medicine 2023The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin...
The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin analogue (Krenning et al. 1989). In the years that followed an Indium-111 (In) labelled somatostatin analogue, chelated with diethylenetriaminepentaacetic acid (DTPA), was successfully developed. Subsequently, In-OctreoScan was introduced worldwide. In the years to come Tc-Tektrotyde became commercially available with easy access. In the last decade, with the increasing use of positron emission tomography (PET) imaging, somatostatin analogues have been labelled with various positron-emitting isotopes, such as Gallium-68 (Ga) and Copper-64 (Cu) (Lewis et al. 1999, Schottelius et al. 2004, Gabriel et al. 2007) e.g Ga-DOTATOC, Ga-DOTATATE Ga-DOTANOC and Cu-DOTATATE. Scintigraphy with these investigational compounds display encouraging good imaging quality amd improved sensitivity in tumor site detection compared with SPECT scintigraphy. Also, other PET radiopharmaceuticals were developed, such as F-dihydroxy-phenyl-alanine (F-DOPA) and C-labelled 5-hydroxytryptophan (C-5-HTP) with encouraging results in terms of visualization of GEP-NETs (Koopmans et al. 2008). After the successful introduction of SRS in the diagnosis and staging of NETs, the next logical step was to increase the administered activity so that the radiopharmaceutical can induce tumor shrinkage in patients who had inoperable and/or metastasized NENs. Therefore, the first peptide receptor radionuclide therapy (PRRT) was performed with high administered activity of [In-DTPA0] octreotide (Krenning et al. 1994a). To make significant advancements in the treatment of somatostatin receptor-positive metastatic disease, more efficient radiolabelled somatostatin analogues were developed with higher affinity to the somatostatin receptor. Treatment with radiolabelled peptides or PRRT is a promising new therapeutic option in the management of inoperable or metastasized NETs. Symptomatic control can be achieved with all In-, Y- and Lu-labelled somatostatin analogue-based PRRT. For objective response and long-lasting duration of response, Y-DOTATOC and Lu-DOTATATE are the most promising radiopharmaceuticals. Side effects of PRRT are few and mild, if adequate kidney protective measures are taken and dose-limits are respected. In a minority of patients, when SRS fails to identify neuroendocrine disease, MIBG scintigraphy and subsequent I-MBG therapy might be an alternative treatment option. Targeted alpha-particle therapy (TAT) has emerged as an alternative treatment option to beta emitters in PRRT. The use of alpha emitters for cancer therapy has two advantages over beta emitter PRRT. The short range of alpha particles of only a few cell diameters (<0.1mm) allows for selective ablation of the target cancer cells, while sparing the surrounding healthy tissue. In addition, the higher linear energy transfer (LET), when compared to conventional beta emitters, results in the formation of complex DNA double-strand and DNA cluster breaks, which ultimately lead to cell death.(Lassmann M et al. Ann ICRP. 2018) Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium-225 (Ac)-DOTATATE and Bismuth-213 (Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, c-DOTATATE, in the treatment of metastatic NENs. Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumors (NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localization of the primary and metastatic disease remains the ultimate goal of research.
Topics: Humans; Radiopharmaceuticals; Receptors, Somatostatin; Gallium Radioisotopes; Iodine Radioisotopes; Copper; Somatostatin; Pancreatic Neoplasms; Neuroendocrine Tumors; DNA; Organometallic Compounds
PubMed: 37658556
DOI: No ID Found -
Frontiers in Endocrinology 2021Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This... (Review)
Review
Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both "cold", particularly octreotide and lanreotide, and "hot" analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with Ga-DOTATATE and Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.
Topics: Adrenal Gland Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Precision Medicine; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 33854479
DOI: 10.3389/fendo.2021.625312 -
Best Practice & Research. Clinical... Sep 2023Neuroendocrine neoplasms are rare and heterogenous group of tumors with varying degrees of clinical presentations and involvement of multiple organ systems in the body.... (Review)
Review
Neuroendocrine neoplasms are rare and heterogenous group of tumors with varying degrees of clinical presentations and involvement of multiple organ systems in the body. In the modern clinical practice somatostatin receptor molecular imaging and targeted radioligand therapy plays a vital role in the diagnosis and management of the disease. Several new and promising radiotracers for NET imaging and theranostics, belonging to various groups and classes are being studied and investigated. This exponential growth of radiotracers poses concerns about the indication, clinical benefit, and safety profile of the agents. We discuss the basis behind these radiotracers clinical use, receptor targeting and intra and inter tumor heterogeneity. Furthermore, role of dual tracer imaging, combination therapy and potential applications of dosimetry in predicting treatment outcome and safety profile is reviewed. Individualized precision medicine with better tumor characterization, maximum therapeutic benefit and minimum toxicity is the way forward for future medicine.
Topics: Humans; Neuroendocrine Tumors; Radiopharmaceuticals; Positron-Emission Tomography; Positron Emission Tomography Computed Tomography; Receptors, Somatostatin
PubMed: 37468403
DOI: 10.1016/j.beem.2023.101797 -
Revista Espanola de Medicina Nuclear E... 2022This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin...
This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin receptors, the selection of patients for radiolabelled peptide therapy (PRRT), the inclusion criteria to benefit from treatment with the minimum possible adverse effects, the administration protocol, follow-up and response evaluation. The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out, and constitute the cornerstone for the development of teragnosis. Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options, and among the future perspectives, there are several lines of research to improve the objective response rate and survival with PRRT, focused on the development of new agonists and somatostatin receptor antagonists, new radionuclides and radiosensitizing combination therapies. In conclusion, PRRT is a great therapeutic, well-tolerated and safe tool with generally mild and self-limited acute side effects, that must be sequenced at the best moment of the evolution of the disease of patients with NET. Candidate patients for PRRT should always be evaluated by a multidisciplinary clinical committee.
Topics: Heterocyclic Compounds, 1-Ring; Humans; Neuroendocrine Tumors; Radioisotopes; Receptors, Somatostatin
PubMed: 34920969
DOI: 10.1016/j.remnie.2021.11.001 -
Journal of Nuclear Medicine : Official... Mar 2024Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to...
Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to somatostatin receptors and are used for palliation of hormonal syndromes and control of tumor growth. The long-acting SSAs octreotide long-acting release and lanreotide are commonly used in the first-line metastatic setting because of their tolerable side effect profile. Radiolabeled SSAs are used both for imaging and for treatment of NETs. Lu-DOTATATE is a β-emitting radiolabeled SSA that has been proven to significantly improve progression-free survival among patients with progressive midgut NETs and is approved for treatment of metastatic gastroenteropancreatic NETs. A key question in management of patients with gastroenteropancreatic and lung NETs is the sequencing of Lu-DOTATATE in relation to other systemic treatments (such as everolimus) or liver-directed therapies. This question is particularly complicated given the heterogeneity of NETs and the near absence of randomized trials comparing active treatment options. This state-of-the-art review examines the evidence supporting use of somatostatin-receptor-targeted treatments within the larger landscape of NET therapy and offers insights regarding optimal patient selection, assessment of benefit versus risk, and treatment sequencing.
Topics: Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Carcinoma, Neuroendocrine; Somatostatin; Octreotide; Neoplasms, Second Primary
PubMed: 38238038
DOI: 10.2967/jnumed.123.265706