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Intracellular signal pathway of somatostatin receptors. SSTR: somatostatin receptor; PTPN: protein tyrosine phosphatase; PI3K: phosphoinositide-3-kinase; AKT: Protein kinase B; AC: adenylyl cyclase
Source publication
Purpose:
The specific indications of somatostatin analogs (SSAs) in patients with neuroendocrine tumor (NET) emerged over the time. The objective of this review is to summarize and discuss the most relevant data concerning long-acting SSAs in NET.
Methods:
A narrative review was performed including publications focusing on therapy with the long-...
Context in source publication
Context 1
... formulations exhibit similar pharmacokinetic and pharmacodynamic properties and have a comparable safety profile [64,65]. LA pasireotide is a promising therapy for Table 2 Efficacy outcomes of non-randomized studies with high dose long-acting somatostatin analogues in neuroendocrine tumors NA not available, SSA somatostatin analogues, OCT octreotide, LAN lanreotide, PFS progression-free survival, CR complete response, PR partial response, SD stable disease, PD progressive disease, OS overall survival, GEP gastroenteropancreatic (Figure 1). Yao et al. in a phase I study, demonstrated that the maximum tolerated dose for pasireotide in patients with advanced NETs is 120 mg, at which dose bradycardia events reached 31% compared to 0% at the 80 mg dose. ...
Citations
... Somatostatin Analogues (SSA) represent the mainstay of systemic treatment for neoplasms originating from neuroendocrine cells, that express somatostatin (SST) receptors (SSTR) on their surface [1,2]. They include a heterogeneous group of neuroendocrine neoplasms (NENs) arising in the gastrointestinal tract, pancreas, lung, and thymus, with the pancreas being the most common site of occurrence [3,4]. ...
... According to the 2022 WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, also pituitary adenomas (pitNET) are included among neoplasms of neuroendocrine origin, since they share with NETs some morphological and ultrastructural features and express the conventional biomarkers of neuroendocrine lineage and differentiation, including SSTRs, which makes them targets for medical therapy with SST analogues (SSA) [6]. SSAs are widely used as medical therapy in both functional and non-functional NETs (including pit-NET), to control hormonal production excess and tumor growth [1,2]. Moreover, the innovative peptide-receptor radionuclide therapy (PRRT) has been demonstrated to be effective for SSTR-positive NETs [7,8]. ...
... However, SS cannot be used for therapeutic purposes due to its rapid blood clearance. This limit has been overcome with the discovery of potent synthetic SST analogues (SSAs) effective as antisecretory and antiproliferative agents that have a different degree of affinity with the five SSTRs: octreotide, lanreotide and pasireotide [1,2,14,[18][19][20]. Specifically, octreotide and lanreotide show high affinity for SST type 2 receptors (SSTR2), especially type 2A receptors (SSTR2A) moderate affinity with SSTR3 and SSTR5 and very low, or absent, affinity in binding SSTR1 and SSTR4. ...
As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.
Neuroendocrine neoplasms (NENs), arising from various sites, present therapeutic challenges. Radioligand therapy (RLT) is effective for unresectable/metastatic NENs with increased somatostatin receptor uptake. While evidence supports RLT's efficacy in midgut NETs, its role in lung NETs remains underexplored. Clinical guidelines place RLT as a third or fourth-line option in this setting. However, in the last years several studies investigated mainly retrospectively effectiveness and safety of RLT in lung NET. The aim of this review is to assess the efficacy and safety of RLT in patients with lung NETs. Following PRISMA guidelines, a systematic review of MEDLINE and EMBASE databases retrieved English articles until March 31, 2023. Inclusion criteria encompassed studies involving RLT in lung NETs with efficacy and safety assessments. Twenty-seven studies met the criteria, totaling 786 patients. The pooled analysis revealed a 25.6% objective response rate and 75.6% disease control rate. Median progression-free survival averaged 20 months, while overall survival averaged 45 months. Factors affecting response included tumor burden, prior treatments, 18F-FDG PET scan uptake, and histological variants. RLT exhibited manageable grade 1/2 adverse effects, predominantly hematological, with Lu177 demonstrating a more favorable profile than Y90. The findings support RLT's effectiveness in lung NETs, offering hope for advanced SSTR-positive patients. Although identifying predictive factors for response remains challenging, RLT retained efficacy even after prior therapies and typical carcinoids displayed a slightly better response than atypical ones. Prospective trials are imperative to establish RLT's definitive efficacy and its place in the therapeutic landscape for lung NETs.
Neuroendocrine tumors (NETs) are a group of well-differentiated heterogeneous neoplasms characterized by slow progression and distinct clinical and biological behavior. In the majority of patients with NET, first-line treatment is represented by somatostatin analogs (SSAs) that, despite being drugs with high tolerability (even at high doses) and providing to carcinoid symptoms control and anti-proliferative effects, may present some side effects, with potential impact on quality of life and nutritional status. The most frequent side effects are represented by gastrointestinal events in particular alterations in bowel habits (diarrhea and constipation), abdominal pain, exocrine pancreatic insufficiency, and cholelithiasis. Considering the relative rarity of NETs, literature about frequency and standard clinical management of adverse events SSA-related is still lacking and heterogeneous. The aim of this review is to arm gastroenterologists and other physicians treating NET patients with essential knowledge on the side effects of SSAs. By identifying and managing these adverse events early, healthcare professionals can offer optimal care, avert foreseeable complications, and ensure the best outcomes for patients. Without such early recognition, there is a risk of diminishing the patient's quality of life and their ability to sustain treatment over time.
Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β–catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host’s gut microbiome interactions is only partially known. The results of SST analogues (SSAs)’ treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.
