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Current Treatment Options in Oncology Mar 2021Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development... (Review)
Review
Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development strategies in this field. Somatostatin receptor type 2 (SSTR2) expression is the hallmark of well-differentiated neuroendocrine tumors (NETs). Somatostatin analogs and peptide receptor radionuclide therapy (PRRT) form the basis of anti-SSTR2 treatment onto new combination strategies, antibody-drug conjugates and bispecific antibodies. Classical pathways involved in NET development (PI3K-Akt-mTOR and antiangiogenics) are reviewed but new potential targets for NET treatment will be explored. Epigenetic drugs have shown clinical activity in monotherapy and preclinical combination strategies are more than attractive. Immunotherapy has shown opposite results in different NEN settings. Although the NOTCH pathway has been targeted with disappointing results, new strategies are being developed. Finally, after years of solid preclinical evidence on different genetically engineered oncolytic viruses, clinical trials for refractory NET patients are now ongoing.
Topics: Angiogenesis Inhibitors; Drug Development; Epigenesis, Genetic; Humans; Immunoconjugates; Immunotherapy; Neuroendocrine Tumors; Oncolytic Viruses; Protein Kinase Inhibitors; Radioisotopes; Receptors, Peptide; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 33786683
DOI: 10.1007/s11864-021-00834-3 -
Endocrine-related Cancer Jun 2018Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with... (Review)
Review
Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affinity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affinity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Neuroendocrine Tumors; Receptors, Somatostatin; Somatostatin
PubMed: 29643113
DOI: 10.1530/ERC-18-0010 -
International Journal of Molecular... Jun 2022Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of...
Somatostatin (also named as growth hormone-inhibiting hormone or somatotropin release-inhibiting factor) is a regulatory peptide important for the proper functioning of the endocrine system, local inflammatory reactions, mood and motor coordination, and behavioral responses to stress. Somatostatin exerts its effects via binding to G-protein-coupled somatostatin receptors of which the fourth subtype (SSTR4) is a particularly important receptor mediating analgesic, anti-inflammatory, and anti-depressant effects without endocrine actions. Thus, SSTR4 agonists are promising drug candidates. Although the knowledge of the atomic resolution-binding modes of SST would be essential for drug development, experimental elucidation of the structures of SSTR4 and its complexes is still awaiting. In the present study, structures of the somatostatin-SSTR4 complex were produced using an unbiased, blind docking approach. Beyond the static structures, the binding mechanism of SST was also elucidated in the explicit water molecular dynamics (MD) calculations, and key binding modes (external, intermediate, and internal) were distinguished. The most important residues on both receptor and SST sides were identified. An energetic comparison of SST binding to SSTR4 and 2 offered a residue-level explanation of receptor subtype selectivity. The calculated structures show good agreement with available experimental results and indicate that somatostatin binding is realized via prerequisite binding modes and an induced fit mechanism. The identified binding modes and the corresponding key residues provide useful information for future drug design targeting SSTR4.
Topics: Analgesics; Phagocytosis; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 35805885
DOI: 10.3390/ijms23136878 -
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 -
Surgery Jan 2020
Topics: Gallium Radioisotopes; Humans; Neuroendocrine Tumors; Receptors, Somatostatin
PubMed: 31629543
DOI: 10.1016/j.surg.2019.05.093 -
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 -
Journal of Neurosurgery Apr 2024The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the...
OBJECTIVE
The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs.
METHODS
A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion.
RESULTS
Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001).
CONCLUSIONS
Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.
Topics: Adult; Male; Female; Humans; Receptors, Somatostatin; Acromegaly; Insulin-Like Growth Factor I; Retrospective Studies; Adenoma; Somatostatin; Pituitary Neoplasms; RNA, Messenger
PubMed: 37856412
DOI: 10.3171/2023.7.JNS23858 -
Pituitary Feb 2017Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but... (Review)
Review
INTRODUCTION
Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients.
DISCUSSION
The mechanisms underlying the so called "SRL resistance" are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a "partial resistance" to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage.
Topics: Acromegaly; Female; Humans; Male; Octreotide; Peptides, Cyclic; Receptors, Somatostatin; Somatostatin
PubMed: 27778296
DOI: 10.1007/s11102-016-0768-4 -
APMIS : Acta Pathologica,... Apr 2023Insulinomas are rare pancreatic neuroendocrine tumours. Most patients can be cured with surgery, but patients with a metastatic disease show impaired survival. The aim...
Insulinomas are rare pancreatic neuroendocrine tumours. Most patients can be cured with surgery, but patients with a metastatic disease show impaired survival. The aim of this study was to evaluate somatostatin receptor (SSTR) 1-5 expression in insulinomas and to correlate the expression profile with clinicopathological variables and with patient outcome. This retrospective study involved 52 insulinoma patients. After histological re-evaluation, formalin-fixed paraffin-embedded tissue samples were processed into tissue microarrays and stained immunohistochemically with monoclonal SSTR1-5 antibodies. All the 52 tumours (49 non-metastatic, 3 metastatic) expressed at least one SSTR subtype. SSTR2 was expressed most frequently (71%), followed by SSTR3 (33%), SSTR1 (27%), SSTR5 (6%) and SSTR4 (0%). SSTR3 expression was associated with a larger tumour size (median diameter 19 mm vs. 13 mm, p = 0.043), and SSTR3 and SSTR5 expression were associated with impaired overall survival [HR 3.532 (95% CI 1.106-11,277), p = 0.033, and HR 6.805 (95% CI 1.364-33.955), p = 0.019 respectively]. Most insulinomas express SSTR2, which may be utilized in diagnostic imaging, and in planning individualized treatment strategies for insulinoma patients. Further studies are needed to clarify the association between SSTR profile and overall survival.
Topics: Humans; Receptors, Somatostatin; Insulinoma; Retrospective Studies; Gene Expression; Antibodies, Monoclonal; Pancreatic Neoplasms
PubMed: 36680557
DOI: 10.1111/apm.13297 -
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