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Journal of Cellular Physiology Apr 2021Recent studies have shown that G protein-coupled receptors (GPCRs), the largest signal-conveying receptor family, are targets for mutations occurring frequently in... (Review)
Review
Recent studies have shown that G protein-coupled receptors (GPCRs), the largest signal-conveying receptor family, are targets for mutations occurring frequently in different cancer types. GPCR alterations associated with cancer development represent significant challenges for the discovery and the advancement of targeted therapeutics. Among the different molecules that can activate GPCRs, we focused on two molecules that exert their biological actions regulating many typical features of tumorigenesis such as cellular proliferation, survival, and invasion: somatostatin and melatonin. The modulation of signaling pathways, that involves these two molecules, opens an interesting scenario for cancer therapy, with the opportunity to act at different molecular levels. Therefore, the aim of this review is the analysis of the biological activity and the therapeutic potential of somatostatin and melatonin, displaying a high affinity for GPCRs, that interfere with cancer development and maintenance.
Topics: Animals; Antineoplastic Agents; Humans; Ligands; Melatonin; Neoplasms; Receptors, Melatonin; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 32989768
DOI: 10.1002/jcp.30062 -
Surgery Jan 2020Neuroendocrine tumors are found throughout the body, including the pancreas. These tumors are phenotypically and genetically heterogeneous and can be difficult to...
BACKGROUND
Neuroendocrine tumors are found throughout the body, including the pancreas. These tumors are phenotypically and genetically heterogeneous and can be difficult to accurately image using current imaging standards. However, positron emission tomography/computed tomography with radiolabeled somatostatin analogs has shown clinical success because many neuroendocrine tumors overexpress somatostatin receptor subtype 2. Unfortunately, patients with poorly differentiated neuroendocrine tumors often have a diminished level of somatostatin receptor subtype 2. We found that histone deacetylase inhibitors can upregulate the functional expression of somatostatin receptor subtype 2.
METHODS
We evaluated the effect of histone deacetylase inhibitors on somatostatin receptor subtype 2 expression at the mRNA and protein level in neuroendocrine tumor cell lines. The effect of histone deacetylase inhibitors on surface somatostatin receptor subtype 2 was also investigated by fluorescence-activated cell sorting analysis. Changes in somatostatin receptor subtype 2 expression in neuroendocrine tumor xenografts after treatment were imaged using Ga68-DOTATATE positron emission tomography/computed tomography.
RESULTS
The functional increase of somatostatin receptor subtype 2 in neuroendocrine tumors after histone deacetylase inhibitor treatment was confirmed through in vitro experiments and small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging. Histone deacetylase inhibitors increased somatostatin receptor subtype 2 transcription and protein expression in neuroendocrine tumor cell lines. Small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging confirmed the enhancement of radiopeptide uptake after histone deacetylase inhibitor administration.
CONCLUSION
This study demonstrates a new method to potentially improve imaging and treatments that target somatostatin receptor subtype 2 in neuroendocrine tumors.
Topics: Animals; Cell Line, Tumor; Cell Separation; Depsipeptides; Flow Cytometry; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Male; Mice; Molecular Imaging; Neuroendocrine Tumors; Organometallic Compounds; Pancreas; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Receptors, Somatostatin; Tissue Array Analysis; Transcription, Genetic; Xenograft Model Antitumor Assays
PubMed: 31629542
DOI: 10.1016/j.surg.2019.05.092 -
European Journal of Nuclear Medicine... Oct 2022To correlate somatostatin receptor (SSTR) and proliferative activity profile (SSTR2, SSTR5, Ki-67) at immunohistochemistry (IHC) with SSTR-PET/CT imaging features in a... (Observational Study)
Observational Study
PURPOSE
To correlate somatostatin receptor (SSTR) and proliferative activity profile (SSTR2, SSTR5, Ki-67) at immunohistochemistry (IHC) with SSTR-PET/CT imaging features in a retrospective series of lung neuroendocrine tumors (NET). Proliferative activity by Ki-67 and F-FDG-PET/CT parameters (when available) were also correlated.
METHODS
Among 551 patients who underwent SSTR-PET/CT with Ga-DOTA-somatostatin analogs (SSA) between July 2011 and March 2020 for lung neuroendocrine neoplasms, 32 patients with a confirmed diagnosis of NET were included. For 14 of them, F-FDG-PET/CT was available. PET/CT images were reviewed by qualitative and semi-quantitative analyses. Immunohistochemistry for SSTR2, SSTR5, and Ki-67 was assessed. Inferential analysis was performed including kappa statistics and Spearman's rank correlation test.
RESULTS
Definitive diagnosis consisted of 26 typical carcinoids-G1 and six atypical carcinoids-G2. Positive SSTR2-IHC was found in 62.5% of samples while SSTR5-IHC positivity was 19.4%. A correlation between SSTR2-IHC and SSTR-PET/CT was found in 24/32 cases (75.0%, p = 0.003): 20 were concordantly positive, 4 concordantly negative. For positive IHC, 100% concordance with SSTR-PET/CT (both positive) was observed, while for negative IHC concordance (both negative) was 33.3%. In 8 cases, IHC was negative while SSTR-PET/CT was positive, even though with low-grade uptake in all but one. A significant correlation between SUV values at SSTR-PET/CT and the SSTR2-IHC scores was found, with low SUV values corresponding to negative IHC and higher SUV values to positive IHC (p = 0.002).
CONCLUSION
This retrospective study showed an overall good agreement between SSTR2-IHC and tumor uptake at SSTR-PET/CT in lung NETs. SSTR-PET/CT SUV values can be used as a parameter of SSTR2 density. Within the limits imposed by the relatively small cohort, our data suggest that SSTR2-IHC may surrogate SSTR-PET/CT in selected lung NET patients for clinical decision making when SSTR-PET/CT is not available.
Topics: Carcinoid Tumor; Fluorodeoxyglucose F18; Gallium Radioisotopes; Humans; Immunohistochemistry; Ki-67 Antigen; Lung; Lung Neoplasms; Neuroendocrine Tumors; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Receptors, Somatostatin; Retrospective Studies; Somatostatin
PubMed: 35674739
DOI: 10.1007/s00259-022-05848-z -
The Journal of Clinical Endocrinology... May 2022Although most tumors in patients with acromegaly are benign and are cured or controlled by surgery and/or first-generation somatostatin receptor ligands therapy, some...
Although most tumors in patients with acromegaly are benign and are cured or controlled by surgery and/or first-generation somatostatin receptor ligands therapy, some can behave more aggressively and are resistant to these standard therapies. Acromegaly, if left untreated, is a rare and chronic disorder, commonly caused by a GH-producing pituitary adenoma and is associated with significant comorbidities and an increased mortality. Transsphenoidal surgery is considered the mainstay of acromegaly management, but medical therapy has an increasingly important role. However, disease activity is not fully controlled in a significant number of patients treated with surgery and/or high-dose first-generation somatostatin receptor ligand monotherapy. In these circumstances, therefore, repeated surgery, second-line medical therapy, and radiotherapy, alone or combined as multimodal therapeutic strategies should be considered, in a patient-centered perspective.
Topics: Acromegaly; Human Growth Hormone; Humans; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 35090028
DOI: 10.1210/clinem/dgac037 -
Annals of Nuclear Medicine Feb 2021This study sets out to evaluate patients with increased uptake in breast lesions on Ga-DOTATATE PET/CT (DOTA PET) and determine the clinical significance of somatostatin...
OBJECTIVE
This study sets out to evaluate patients with increased uptake in breast lesions on Ga-DOTATATE PET/CT (DOTA PET) and determine the clinical significance of somatostatin receptor (SSTR) positive breast lesions.
METHODS
We retrospectively evaluated all patients with increased SSTR uptake in breast lesions on DOTA PET. Patients with physiological (e.g., lactation) or normal variant breast uptake (e.g., mild diffuse glandular uptake) were excluded. The maximum standard uptake value (SUVmax) was calculated using a manually drawn region of interest in the most intense uptake of breast lesions. All lesions were correlated with breast imaging, including mammography and ultrasonography. Histopathological correlation was performed if the lesion was suspicious for malignancy. Lesions were followed up radiologically (1-8 years).
RESULTS
Out of 1573 retrospectively analyzed DOTA PET scans, the incidence of SSTR + breast lesions was measured as 1.1% (n = 18); however, 4 of 18 patients were excluded due to the lack of final diagnosis of lesions. The median age was 35 (range 14-58 years), and all patients were female. The median SUVmax of SSTR + breast lesions was 5.2 (range 1.5-12.6) for a total of 14 patients. Twelve patients had a single SSTR + breast lesion, while 2 patients had multiple SSTR + lesions on bilateral breasts. In 6 patients, single SSTR + lesions were considered as fibroadenoma; in 2 patients, multiple SSTR + lesions were considered as metastases of NET, based on correlative breast imaging. In 6 patients, histopathological confirmation was needed for the final diagnosis. Histopathologic findings confirmed fibroadenoma in 4 patients by biopsy, in 1 patient with surgical removal of the lesion. The last patient who had a history of IDC was diagnosed with a recurrence of IDC with biopsy. The median SUVmax was 5.1 (range 1.5-9.4) for malignant breast lesions and 5.4 (range 2.2-12.6) for benign breast lesions.
CONCLUSION
SSTR + breast lesions on DOTA PET are rarely seen in clinical practice. Uptakes of breast lesions in our cases were variable and not useful for differential diagnosis of lesions. It seems that SSTR + breast lesions should be evaluated with clinical and radiological characteristics, and correlative breast imaging and/or histopathological verification should be performed for suspicious lesions to avoid misdiagnosis.
Topics: Adolescent; Adult; Breast; Female; Fibroadenoma; Gallium Radioisotopes; Humans; Image Processing, Computer-Assisted; Middle Aged; Neoplasm Recurrence, Local; Octreotide; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Receptors, Somatostatin; Retrospective Studies
PubMed: 33400149
DOI: 10.1007/s12149-020-01570-8 -
The Journal of Endocrinology Mar 2024Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the... (Review)
Review
Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the thorax (lungs and thymus), thus representing a well-established target for medical treatment with SST ligands (SRLs). However, the response to SRLs is highly heterogeneous between tumors. Two main factors can contribute to this variability: (i) the differential SST expression among tumor types and (ii) the differential expression/modulation of the SST-related intracellular machinery. In this literature review, we provide an overview of available data on the variable expression of SSTs in pituitary tumors and NENs, together with the resulting clinical implications. Moreover, we aim to describe the complex intracellular machinery involved in SST signaling and trafficking. Particularly, we will focus on β-arrestins and describe their role in receptor internalization and recycling, as well as the various functions of these scaffold molecules in tumor pathogenesis and progression. This review highlights the interplay between membrane receptors and intracellular machinery, together with its role in determining the clinical behavior of the tumor and the response to treatment in patients with pituitary tumors or NENs.
Topics: Humans; Receptors, Somatostatin; Pituitary Neoplasms; Neuroendocrine Tumors
PubMed: 38224333
DOI: 10.1530/JOE-23-0298 -
Advances in Therapy Oct 2023People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver...
INTRODUCTION
People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver or as self-injection via a proprietary or generic device. Injection device attributes that contribute to ease of use and storage, minimise preparation requirements, and reduce injection pain are associated with improved adherence and more favourable therapeutic outcomes. The aim of this study was to assess current opinion surrounding favourable SRL device attributes for people living with acromegaly and NETs as well as that of their caregivers.
METHODS
Participants (healthcare professionals [HCPs] and patients/non-HCP caregivers) from 11 countries were invited to answer survey questions related to their demographic, experience, and preferences as they relate to the real-world use of injectable SRL devices. Questions were developed based on review of available literature and meetings with a Scientific Committee.
RESULTS
Device attributes preferred by the patient/non-HCP caregiver group (n = 211) included confidence that the correct drug amount is delivered (76%), quick administration with minimal pain/discomfort (68%), and device safety (needle-safety and low risk of contamination; 53%). Device attributes preferred by HCPs (n = 52) were quick administration with minimal pain/discomfort (69%), correct use is easy to learn, confidence in handling the device (63%), and confidence that the correct drug amount is delivered (62%).
CONCLUSION
The results identified key features of injection devices for SRL therapy which merit consideration for optimal management and underscore the importance of patient partnership in treatment decisions.
Topics: Humans; Acromegaly; Somatostatin; Receptors, Somatostatin; Neuroendocrine Tumors; Ligands; Pain
PubMed: 37573277
DOI: 10.1007/s12325-023-02627-6 -
Journal of Nuclear Cardiology :... Jun 2021
Topics: Fluorodeoxyglucose F18; Humans; Myocarditis; Organometallic Compounds; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Receptors, Somatostatin; Sarcoidosis; Sensitivity and Specificity
PubMed: 31332660
DOI: 10.1007/s12350-019-01824-7 -
Radiologic Clinics of North America Sep 2021
Review
Topics: Humans; Neuroendocrine Tumors; Positron-Emission Tomography; Radioactive Tracers; Radiopharmaceuticals; Receptors, Somatostatin
PubMed: 34392919
DOI: 10.1016/j.rcl.2021.05.006 -
Pediatric Radiology Jun 2020In recent years, new somatostatin receptor agents (SSTRs) have become available for diagnostic imaging and therapy in neuroendocrine tumors. The novel SSTR ligand... (Review)
Review
In recent years, new somatostatin receptor agents (SSTRs) have become available for diagnostic imaging and therapy in neuroendocrine tumors. The novel SSTR ligand DOTA-DPhel-Tyr3-octreotate (Dotatate) in particular can be linked with Gallium for diagnostic imaging purposes, and with the β-emitter Lutetium for radiotherapy in the setting of neuroendocrine tumors. Dotatate imaging offers distinct advantages in the evaluation of neuroendocrine tumors compared to standard techniques, including greater target-to-background ratio and lesion conspicuity, high sensitivity/specificity, improved spatial resolution with positron emission tomography (PET)/CT or PET/MR, and decreased radiation exposure. Although currently off-label in pediatrics, Dotatate theranostics in children are being explored, most notably in the setting of neuroblastoma and hereditary neuroendocrine syndromes. This article provides a multicenter case series of Dotatate imaging and therapy in pediatric patients in order to highlight the spectrum of potential clinical applications.
Topics: Child; Contrast Media; Humans; Multimodal Imaging; Neuroblastoma; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity
PubMed: 32495176
DOI: 10.1007/s00247-020-04688-z