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Cancer Science Jun 2022Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis... (Review)
Review
Theranostics is a term coined by combining the words "therapeutics" and "diagnostics," referring to single chemical entities developed to deliver therapy and diagnosis simultaneously. Neuroendocrine tumors are rare cancers that occur in various organs of the body, and they express neuroendocrine factors such as chromogranin A and somatostatin receptor. Somatostatin analogs bind to somatostatin receptor, and when combined with diagnostic radionuclides, such as gamma-emitters, are utilized for diagnosis of neuroendocrine tumor. Somatostatin receptor scintigraphy when combined with therapeutic radionuclides, such as beta-emitters, are effective in treating neuroendocrine tumor as peptide receptor radionuclide therapy. Somatostatin receptor scintigraphy and peptide receptor radionuclide therapy are some of the most frequently used and successful theranostics for neuroendocrine tumor. In Japan, radiopharmaceuticals are regulated under a complex law system, creating a significant drug lag, which is a major public concern. It took nearly 10 years to obtain the approval for somatostatin receptor scintigraphy and peptide receptor radionuclide therapy use by the Japanese government. In 2021, Lu-DOTATATE (Lutathera), a drug for peptide receptor radionuclide therapy, was covered by insurance in Japan. In this review, we summarize the history of the development of neuroendocrine tumor theranostics and theranostics in general, as therapeutic treatment for cancer in the future. Furthermore, we briefly address the Japanese point of view regarding the development of new radiopharmaceuticals.
Topics: Humans; Neuroendocrine Tumors; Positron-Emission Tomography; Precision Medicine; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 35271754
DOI: 10.1111/cas.15327 -
Frontiers in Endocrinology 2022Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and... (Review)
Review
Molecular therapeutic targets in growth hormone (GH)-secreting adenomas range from well-characterized surface receptors that recognize approved drugs, to surface and intracellular markers that are potential candidates for new drug development. Currently available medical therapies for patients with acromegaly bind to somatostatin receptors, GH receptor, or dopamine receptors, and lead to attainment of disease control in most patients. The degree of control is variable: however, correlates with both disease aggressiveness and tumor factors that predict treatment response including somatostatin receptor subtype expression, granulation pattern, kinases and their receptors, and other markers of proliferation. A better understanding of the mechanisms underlying these molecular markers and their relationship to outcomes holds promise for expanding treatment options as well as a more personalized approach to treating patients with acromegaly.
Topics: Humans; Acromegaly; Adenoma; Receptors, Somatostatin; Growth Hormone-Secreting Pituitary Adenoma; Pituitary Neoplasms
PubMed: 36545335
DOI: 10.3389/fendo.2022.1068061 -
Journal of Nuclear Medicine : Official... Sep 2017Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the... (Review)
Review
Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the introduction of peptide receptor radionuclide therapy with radiolabeled sstr agonists, such as [Y-DOTA,Tyr]octreotide or [Lu-DOTA,Tyr]octreotide (Y- or Lu-DOTATOC, respectively) and [Lu-DOTA,Tyr]octreotate (Lu-DOTATATE). PET/CT with Ga-labeled sstr agonists, such as Ga-DOTATOC, Ga-DOTATATE, and [Ga-DOTA,1-Nal]octreotide (Ga-DOTANOC), plays an important role in staging and restaging neuroendocrine tumors. Most importantly, sstr scintigraphy and sstr PET/CT can distinguish patients who will qualify for and benefit from peptide receptor radionuclide therapy. This characteristic of sstr targeting is important because it allows a personalized treatment approach (theranostic approach). Until recently, it was thought that internalization of the radiolabeled agonist was mandatory for sstr-mediated imaging and therapy. It was Ginj et al. who proposed in 2006 the paradigm shift that radiolabeled sstr antagonists may perform better than agonists despite the lack of internalization. Despite the rather limited number of head-to-head comparisons of sstr antagonists and agonists, the superiority of sstr antagonists was demonstrated in several cases. From a small library of sstr antagonists, the analog JR11 (Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH), an antagonist with selectivity for sstr subtype 2, showed the best overall characteristics for sstr subtype 2 targeting and was therefore selected for clinical translation. JR11 is under clinical development as a PET imaging agent when labeled with Ga (Ga-NODAGA-JR11 or Ga-OPS202) and as a therapeutic agent when labeled with Lu (Lu-DOTA-JR11 or Lu-OPS201). In this article, we discuss the development and current status of radiolabeled sstr antagonists. Evidence based on preclinical work, on quantitative in vivo autoradiography of human tumor slices, and on human data now supports a shift to sstr antagonists.
Topics: Animals; Diagnostic Imaging; Drug Discovery; Humans; Isotope Labeling; Molecular Targeted Therapy; Receptors, Somatostatin
PubMed: 28864614
DOI: 10.2967/jnumed.116.186783 -
Nuclear Medicine Review. Central &... 2016Neuroendocrine neoplasms (NENs) show wide spectrum of clinical course - from benign biological potential to recurrences and rapidly progressive disease. Somatostatin... (Review)
Review
Neuroendocrine neoplasms (NENs) show wide spectrum of clinical course - from benign biological potential to recurrences and rapidly progressive disease. Somatostatin analogs that bind to somatostatin receptor are part of the therapy; detection and evaluation of activation of somatostatin receptor subtypes are part of the process of new therapy induction. When using RT-PCR method and immunohistochemistry, it is possible to detect more than two SSTR subtypes in majority or all neuroendo-crine neoplasms regardless tumor origin. Generally with some exceptions, from the viewpoint of tumor grade - apart the site of origin, there is a tendency to decrease the percentage of SSTRs expression; 100% (G1, 2)-85.7% (G3) for SSTR 1; 81.8% (G1, 2)-61.9% (G3) for SSTR 2; 54.5% (G1, 2)-52.4% (G3) for SSTR 3; 9% (G1, 2)-4.8% (G3) for SSTR 5. Different studies indi-cate significant differences in the expression of SSTR 1 and 2A and 2B between NEC G3 small cell type and non-small cell type. Further research on SSTRs expression in NEN could serve as base to development and improvement of somatostatin analogs' pharmacotherapy in patients with unsatisfactory course.
Topics: Gene Expression Regulation, Neoplastic; Humans; Neuroendocrine Tumors; Receptors, Somatostatin
PubMed: 27479788
DOI: 10.5603/NMR.2016.0022 -
Journal of Nuclear Medicine : Official... Sep 2017The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic... (Review)
Review
The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic compounds. Whole-body scintigraphy with In-pentetreotide has revolutionized the diagnosis and staging of NETs and the evaluation of treatment outcomes. At present, diagnostic accuracy with positron-emitting radionuclides is greater than 90%. Peptide receptor radionuclide therapy (PRRT) has become a well-accepted treatment for patients with well-differentiated inoperable or metastatic NETs and disease progression after first-line treatment. Disease control rates (complete or partial remission or stable disease in patients with formerly progressive disease) of up to 95%, with a low incidence of long-term hematologic and renal toxicity, have been reported. In a recently published randomized trial, compared with intensified treatment of midgut NETs with long-acting and repeatable octreotide, PRRT reduced the hazard of disease progression and death by 79%. Upcoming developments in PRRT include the use of somatostatin receptor antagonists and α-emitting radionuclides, which may further enhance treatment outcomes.
Topics: Animals; Diagnostic Imaging; Drug Discovery; Humans; Molecular Targeted Therapy; Receptors, Somatostatin; Safety
PubMed: 28864613
DOI: 10.2967/jnumed.117.191015 -
BioMed Research International 2015Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have... (Review)
Review
Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have been identified, with SSTR2 showing the highest affinity for natural SST and synthetic SST analogs. Most neuroendocrine tumors (NETs) have high expression levels of SSTRs, which opens the possibility for tumor imaging and therapy with radiolabeled SST analogs. A number of tracers have been developed for the diagnosis, staging, and treatment of NETs with impressive results, which facilitates the applications of human SSTR subtype 2 (hSSTr2) reporter gene based imaging and therapy in SSTR negative or weakly positive tumors to provide a novel approach for the management of tumors. The hSSTr2 gene can act as not only a reporter gene for in vivo imaging, but also a therapeutic gene for local radionuclide therapy. Even a second therapeutic gene can be transfected into the same tumor cells together with hSSTr2 reporter gene to obtain a synergistic therapeutic effect. However, additional preclinical and especially translational and clinical researches are needed to confirm the value of hSSTr2 reporter gene based imaging and therapy in tumors.
Topics: Diagnostic Imaging; Humans; Neoplasm Staging; Neuroendocrine Tumors; Radioisotopes; Receptors, Somatostatin; Somatostatin
PubMed: 25879040
DOI: 10.1155/2015/917968 -
International Journal of Molecular... Dec 2023Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in endocrine and non-endocrine tissues, immune cells and the central nervous system (CNS).... (Review)
Review
Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in endocrine and non-endocrine tissues, immune cells and the central nervous system (CNS). Post-release from secretory or immune cells, the first most appreciated role that SST exhibits is the antiproliferative effect in target tissue that served as a potential therapeutic intervention in various tumours of different origins. The SST-mediated in vivo and/or in vitro antiproliferative effect in the tumour is considered direct via activation of five different somatostatin receptor subtypes (SSTR1-5), which are well expressed in most tumours and often more than one receptor in a single cell. Second, the indirect effect is associated with the regulation of growth factors. SSTR subtypes are crucial in tumour diagnosis and prognosis. In this review, with the recent development of new SST analogues and receptor-specific agonists with emerging functional consequences of signaling pathways are promising therapeutic avenues in tumours of different origins that are discussed.
Topics: Humans; Receptors, Somatostatin; Somatostatin; Growth Hormone; Neoplasms; Biology
PubMed: 38203605
DOI: 10.3390/ijms25010436 -
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 -
British Journal of Pharmacology Apr 2014The biological actions of somatostatin are mediated by a family of five GPCRs, named sst1 to sst5 . Somatostatin receptors exhibit equally high-binding affinities to... (Review)
Review
The biological actions of somatostatin are mediated by a family of five GPCRs, named sst1 to sst5 . Somatostatin receptors exhibit equally high-binding affinities to their natural ligand somatostatin-14 and largely overlapping distributions. The overexpression of somatostatin receptors in human tumours is the molecular basis for diagnostic and therapeutic application of the stable somatostatin analogues octreotide, lanreotide and pasireotide. The efficiency of somatostatin receptor signalling is tightly regulated and ultimately limited by the coordinated phosphorylation and dephosphorylation of intracellular carboxyl-terminal serine and threonine residues. Here, we review and discuss recent progress in the generation and application of phosphosite-specific antibodies for human sst2 and sst5 receptors. These phosphosite-specific antibodies are unique tools to monitor the spatial and temporal dynamics of receptors phosphorylation and dephosphorylation. Using a combined approach of phosphosite-specific antibodies and siRNA knock-down screening, relevant kinases and phosphatases were identified. Emerging evidence suggests distinct mechanisms of agonist-selective fine-tuning for individual somatostatin receptors. The recently uncovered differences in phosphorylation and dephosphorylation of these receptors may hence be of physiological significance in mediating responses to acute, persistent or repeated stimuli in a variety of target tissues.
Topics: Amino Acid Sequence; Animals; Antibodies; Humans; Ligands; Molecular Sequence Data; Phosphorylation; RNA Interference; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 24328848
DOI: 10.1111/bph.12551 -
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