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In vitro studies using autoradiography I-labelled somatostatin analogue; fig. In addition, they are homogenously distributed on the surface of the NETs and thus are an ideal target for molecular imaging and therapy [ 2 ]. Importantly, the radioisotope has to be linked to the molecule, which targets the specific receptors. The principal composition of the administered molecule for diagnostic purposes in vivo is shown in figure 2.

The clinical significance of the most important peptide receptor for molecular imaging and therapy in NET will be reviewed here. In addition, new developments will be discussed. Somatostatin receptors SSTR represent one of the first examples of receptor targeting in humans. The only exceptions are insulin secreting NET insulinomas and medullary thyroid cancer where other receptors such as GLP-1 and CCK-2 play an important role see the corresponding section below. The most important effect of somatostatin and its analogues with agonistic properties is inhibitory, both physiologically and in tumours.

In NET, somatostatin receptor agonists inhibit hormonal secretion, which is well established in secreting gastroenteropancreatic neuroendocrine tumours GEP-NET like carcinoids, gastrinomas, VIP-oma and glucagonoma, but is less effective in insulinomas [ 5 ]. Furthermore, randomised controlled trials have shown that somatostatin analogues have an antitumour effect by significantly extending the progression-free survival in secreting [ 6 ] and non-secreting NET [ 7 ] by binding to the somatostatin receptors [ 6 — 8 ], however, without affecting overall survival.

Although the anti-proliferative effect of somatostatin analogues is not completely elucidated, they exert an anti-angiogenic effect by inhibiting endothelial cell proliferation and the development of new tumour-associated blood vessels [ 9 ]. This may contribute to tumour size reduction [ 10 ].

For the in vitro somatostatin receptor assessment, two reliable methods are established. It can, therefore, be helpful to determine whether a patient is a candidate for in vivo targeting of SSTR. It allows high-quality imaging with improved sensitivity as early as 45 minutes after injection of the radiotracer, provides higher spatial resolution and enables better absolute quantification of tracer uptake determination of the standardised uptake value SUV. SSTR imaging is indicated in the following clinical situations: 1 as a diagnostic tool in order to find a primary NET i.

The advantage of this molecular imaging is two-fold: 1 confirmation of the presence of SSTR in vivo and 2 a high sensitivity and specificity for NET in the case of an unclear lesion in conventional imaging. Side effects of the application are rare and include nausea and only very rarely vomitus. Glucose metabolism is the main energy source for most cells. Therefore, 18 F-Fluorodeoxyglucose 18 F-FDG is able to visualise intracellular increased glucose turnover in patients with neoplastic disease. As such, 18 F-FDG is not routinely used for diagnostic purposes.

However, high glucose metabolism can be documented in poorly differentiated NETs G3 and is usually associated with a poor prognosis. In addition, there are data suggesting the usefulness of this modality to localise medullary thyroid carcinoma, benign insulinomas, paragangliomas and phaeochromocytomas. In contrast, a positive result of a SSTR imaging procedure can have immediate therapeutic consequences. In such patients, peptide receptor radionuclide therapy PRRT can be administered with the appropriate beta-emitter e.

The clinical success of somatostatin receptor targeting of neuroendocrine tumours has stimulated the search for other peptide receptors suitable for similar applications.

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This receptor is also a member of the G-protein-coupled receptor family [ 21 ] and its expression has been characterised in normal human tissues. It has been found in the pancreatic islets and acini, stomach, small and large intestinal myenteric plexus, lung and kidney vasculature, breast parenchyma, heart, brainstem, hypothalamus, neurohypophysis and meninges.

1. Introduction

GLP-1 receptor activation upon agonist binding stimulates adenylate cyclase and phospholipase C, with subsequent activation of protein kinase A and C, respectively [ 22 ]. The glucagon-like peptide GLP-1 is an incretin hormone mainly produced in the enteroendocrine L cells of the ileum and colon in response to nutrient intake and is one of the most important glucose-dependent insulin secretagogues.

In addition to the glucose-dependent increase in insulin secretion, GLP-1 inhibits glucagon secretion, gastric emptying and food ingestion, and promotes enhanced glucose disposal through neural mechanisms [ 22 ]. However, the natural ligand GLP-1 30 amino acids peptide has unfavourable characteristics for successful in vivo targeted imaging as it is degraded in the human blood by dipeptidyl-peptidase-4 [ 24 ] and therefore has a plasma half-life of less than two minutes.

Hypothesis and Theory ARTICLE

In search of a more favourable analogue, exendin-4 was identified. This peptide is metabolically resistant to dipeptidyl-peptidase-4 degradation [ 25 ]. Consequently, Exenatide, a synthetic exendin-4 was developed, which is primarily an FDA-approved medication established for the treatment of type 2 diabetes mellitus.

TRACO 2017 - Clinical trials and Precision Medicine

Benign insulinomas are usually located in the pancreas. They are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in adults [ 27 ]. At present, surgery remains the only curative treatment. Pancreas-preserving surgery such as limited segmental resection or enucleation is considered the treatment of choice [ 28 — 30 ]. Therefore, the exact preoperative localisation of insulinomas is critical in order to plan surgical strategy and improve postoperative outcomes.

Reubi et. The density of GLP-1R expression in insulinoma was approximately a five-fold increase compared to a normal pancreatic B-cell [ 13 ]; fig. This is of particular importance since SSTR density is comparatively low in benign insulinomas. Consequently, in vivo SSTR imaging for insulinomas is often negative. The high GLP-1 receptor density makes it an ideal target for molecular imaging, fulfilling the critical prerequisite for successful in vivo targeting [ 2 , 33 ].

In , the first two patients who underwent GLP-1 receptor scintigraphy were published as a letter in the New England Journal of Medicine. Both patients suffered from severe endogenous hyperinsulinaemic hypoglycaemia and previous conventional imaging or selective arterial stimulation and venous sampling was negative or inconclusive.

Peptides and Non Peptides of Oncologic and Neuroendocrine Relevance

In both patients, GLP-1R detected a focal lesion which was surgically resected, and histologic analysis of surgically removed tissues confirmed the diagnosis of a benign insulinoma containing a high GLP-1R density [ 34 ]. In a proof of principle study, In-DOTA-exendin-4 was prospectively administered to six patients [ 35 ], all of whom presented with neuroglycopenic symptoms due to endogenous hyperinsulinaemic hypoglycaemia.

GLP-1R scintigraphy correctly detected the insulinoma in all six consecutive patients. In vitro autoradiography of GLP-1R showed a density of GLP-1R in the range as previously described [ 2 ], whereas somatostatin receptor status revealed low density of somatostatin type 1 receptors [ 35 ]. The first prospective multicentre study included 30 patients with proven endogenous hyperinsulinaemic hypoglycaemia who underwent In-DTPA-exendin-4 imaging GLP-1R scanning. Seven patients were operated because GLP-1R imaging was the only method that showed a suspicious lesion in the pancreas.

Five of these patients had a confirmed insulinoma with normalisation of blood sugar levels after surgery, supporting the clinical value of GLP-1R imaging. Based on these promising data, a prospective study including 52 consecutive patients was conducted at the University Hospital of Basel. This requires the assessment of blood glucose, C-peptide and insulin levels in a standardised fasting test. If an endogenous hyperinsulinaemic hypoglycaemia is confirmed, a GLP-1R molecular imaging is indicated. These side effects are usually confined to the first hour after injection.

During the first five hours after the injection of a DOTA-Exendin-4 Tracer, a decrease in blood glucose levels can occur. Therefore, the continued infusion of intravenous glucose administration is recommended during the procedure. It was thought that the internalisation of the tracer is essential for a high accumulation and long-lasting retention of the radiotracer into the tumour cells.

The paradigm shifted when in vitro and in vivo data showed that a higher tumour uptake and longer tumour retention could be obtained with radiolabelled SSTR antagonists without documented internalisation [ 38 ]. Based on in vitro studies, it is likely that radiolabelled SSTR antagonists exhibit a higher number of potential binding sites on the receptor, thereby increasing the tumour uptake [ 38 , 39 ]. This was confirmed with autoradiographic studies on human tumour sections [ 40 ].


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Importantly, the amount of antagonist peptide administered may further enhance the therapeutic index. In fact, it was shown that increasing peptide mass decreases the background dose for a constant tumour dose [ 46 ]. A characteristic feature of these tumours is the high incidence and expression of CCK receptors and the relatively low incidence and density of SSTR [ 2 ].

The only curative therapeutic option is surgery.

There is, therefore, an unmet need for a better diagnostic and therapeutic tool. By labelling a minigastrin ligand for CCK-receptors with Lu, the first proof of principle study with six patients with metastatic MTC was performed with encouraging results [ 48 ]. No clinical study in humans has yet been performed. In addition, the successful administration of these molecules with radioisotopes, which have positron emitting properties, has been extensively and successfully explored.

Since virtually all benign insulinomas express GLP-1Rs, this should be the imaging modality of choice in cases where conventional morphological imaging fails. No financial support and no other potential conflict of interest relevant to this article was reported. In addition, they are homogenously distributed on the surface of the NETs and thus are an ideal target for molecular imaging and therapy [ 2 ].

Importantly, the radioisotope has to be linked to the molecule, which targets the specific receptors. The principal composition of the administered molecule for diagnostic purposes in vivo is shown in figure 2. The clinical significance of the most important peptide receptor for molecular imaging and therapy in NET will be reviewed here. In addition, new developments will be discussed. Somatostatin receptors SSTR represent one of the first examples of receptor targeting in humans. The only exceptions are insulin secreting NET insulinomas and medullary thyroid cancer where other receptors such as GLP-1 and CCK-2 play an important role see the corresponding section below.

The most important effect of somatostatin and its analogues with agonistic properties is inhibitory, both physiologically and in tumours. In NET, somatostatin receptor agonists inhibit hormonal secretion, which is well established in secreting gastroenteropancreatic neuroendocrine tumours GEP-NET like carcinoids, gastrinomas, VIP-oma and glucagonoma, but is less effective in insulinomas [ 5 ].

Furthermore, randomised controlled trials have shown that somatostatin analogues have an antitumour effect by significantly extending the progression-free survival in secreting [ 6 ] and non-secreting NET [ 7 ] by binding to the somatostatin receptors [ 6 — 8 ], however, without affecting overall survival. Although the anti-proliferative effect of somatostatin analogues is not completely elucidated, they exert an anti-angiogenic effect by inhibiting endothelial cell proliferation and the development of new tumour-associated blood vessels [ 9 ].

Somatostatin in Clinical Endocrinology | SpringerLink

This may contribute to tumour size reduction [ 10 ]. For the in vitro somatostatin receptor assessment, two reliable methods are established. It can, therefore, be helpful to determine whether a patient is a candidate for in vivo targeting of SSTR. It allows high-quality imaging with improved sensitivity as early as 45 minutes after injection of the radiotracer, provides higher spatial resolution and enables better absolute quantification of tracer uptake determination of the standardised uptake value SUV. SSTR imaging is indicated in the following clinical situations: 1 as a diagnostic tool in order to find a primary NET i.

The advantage of this molecular imaging is two-fold: 1 confirmation of the presence of SSTR in vivo and 2 a high sensitivity and specificity for NET in the case of an unclear lesion in conventional imaging. Side effects of the application are rare and include nausea and only very rarely vomitus. Glucose metabolism is the main energy source for most cells. Therefore, 18 F-Fluorodeoxyglucose 18 F-FDG is able to visualise intracellular increased glucose turnover in patients with neoplastic disease.

As such, 18 F-FDG is not routinely used for diagnostic purposes. However, high glucose metabolism can be documented in poorly differentiated NETs G3 and is usually associated with a poor prognosis. In addition, there are data suggesting the usefulness of this modality to localise medullary thyroid carcinoma, benign insulinomas, paragangliomas and phaeochromocytomas. In contrast, a positive result of a SSTR imaging procedure can have immediate therapeutic consequences.

In such patients, peptide receptor radionuclide therapy PRRT can be administered with the appropriate beta-emitter e. The clinical success of somatostatin receptor targeting of neuroendocrine tumours has stimulated the search for other peptide receptors suitable for similar applications. This receptor is also a member of the G-protein-coupled receptor family [ 21 ] and its expression has been characterised in normal human tissues.

It has been found in the pancreatic islets and acini, stomach, small and large intestinal myenteric plexus, lung and kidney vasculature, breast parenchyma, heart, brainstem, hypothalamus, neurohypophysis and meninges. GLP-1 receptor activation upon agonist binding stimulates adenylate cyclase and phospholipase C, with subsequent activation of protein kinase A and C, respectively [ 22 ]. The glucagon-like peptide GLP-1 is an incretin hormone mainly produced in the enteroendocrine L cells of the ileum and colon in response to nutrient intake and is one of the most important glucose-dependent insulin secretagogues.

In addition to the glucose-dependent increase in insulin secretion, GLP-1 inhibits glucagon secretion, gastric emptying and food ingestion, and promotes enhanced glucose disposal through neural mechanisms [ 22 ]. However, the natural ligand GLP-1 30 amino acids peptide has unfavourable characteristics for successful in vivo targeted imaging as it is degraded in the human blood by dipeptidyl-peptidase-4 [ 24 ] and therefore has a plasma half-life of less than two minutes.

In search of a more favourable analogue, exendin-4 was identified. This peptide is metabolically resistant to dipeptidyl-peptidase-4 degradation [ 25 ].

Description

Consequently, Exenatide, a synthetic exendin-4 was developed, which is primarily an FDA-approved medication established for the treatment of type 2 diabetes mellitus. Benign insulinomas are usually located in the pancreas.


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  • They are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in adults [ 27 ]. At present, surgery remains the only curative treatment. Pancreas-preserving surgery such as limited segmental resection or enucleation is considered the treatment of choice [ 28 — 30 ]. Therefore, the exact preoperative localisation of insulinomas is critical in order to plan surgical strategy and improve postoperative outcomes. Reubi et.

    The density of GLP-1R expression in insulinoma was approximately a five-fold increase compared to a normal pancreatic B-cell [ 13 ]; fig. This is of particular importance since SSTR density is comparatively low in benign insulinomas. Consequently, in vivo SSTR imaging for insulinomas is often negative. The high GLP-1 receptor density makes it an ideal target for molecular imaging, fulfilling the critical prerequisite for successful in vivo targeting [ 2 , 33 ]. In , the first two patients who underwent GLP-1 receptor scintigraphy were published as a letter in the New England Journal of Medicine.

    Both patients suffered from severe endogenous hyperinsulinaemic hypoglycaemia and previous conventional imaging or selective arterial stimulation and venous sampling was negative or inconclusive. In both patients, GLP-1R detected a focal lesion which was surgically resected, and histologic analysis of surgically removed tissues confirmed the diagnosis of a benign insulinoma containing a high GLP-1R density [ 34 ]. In a proof of principle study, In-DOTA-exendin-4 was prospectively administered to six patients [ 35 ], all of whom presented with neuroglycopenic symptoms due to endogenous hyperinsulinaemic hypoglycaemia.

    GLP-1R scintigraphy correctly detected the insulinoma in all six consecutive patients. In vitro autoradiography of GLP-1R showed a density of GLP-1R in the range as previously described [ 2 ], whereas somatostatin receptor status revealed low density of somatostatin type 1 receptors [ 35 ]. The first prospective multicentre study included 30 patients with proven endogenous hyperinsulinaemic hypoglycaemia who underwent In-DTPA-exendin-4 imaging GLP-1R scanning. Seven patients were operated because GLP-1R imaging was the only method that showed a suspicious lesion in the pancreas.

    Five of these patients had a confirmed insulinoma with normalisation of blood sugar levels after surgery, supporting the clinical value of GLP-1R imaging. Based on these promising data, a prospective study including 52 consecutive patients was conducted at the University Hospital of Basel. This requires the assessment of blood glucose, C-peptide and insulin levels in a standardised fasting test.

    If an endogenous hyperinsulinaemic hypoglycaemia is confirmed, a GLP-1R molecular imaging is indicated. These side effects are usually confined to the first hour after injection. During the first five hours after the injection of a DOTA-Exendin-4 Tracer, a decrease in blood glucose levels can occur. Therefore, the continued infusion of intravenous glucose administration is recommended during the procedure.

    It was thought that the internalisation of the tracer is essential for a high accumulation and long-lasting retention of the radiotracer into the tumour cells. The paradigm shifted when in vitro and in vivo data showed that a higher tumour uptake and longer tumour retention could be obtained with radiolabelled SSTR antagonists without documented internalisation [ 38 ]. Based on in vitro studies, it is likely that radiolabelled SSTR antagonists exhibit a higher number of potential binding sites on the receptor, thereby increasing the tumour uptake [ 38 , 39 ].

    This was confirmed with autoradiographic studies on human tumour sections [ 40 ]. Importantly, the amount of antagonist peptide administered may further enhance the therapeutic index. In fact, it was shown that increasing peptide mass decreases the background dose for a constant tumour dose [ 46 ]. A characteristic feature of these tumours is the high incidence and expression of CCK receptors and the relatively low incidence and density of SSTR [ 2 ].

    The only curative therapeutic option is surgery. There is, therefore, an unmet need for a better diagnostic and therapeutic tool. By labelling a minigastrin ligand for CCK-receptors with Lu, the first proof of principle study with six patients with metastatic MTC was performed with encouraging results [ 48 ]. No clinical study in humans has yet been performed.

    In addition, the successful administration of these molecules with radioisotopes, which have positron emitting properties, has been extensively and successfully explored. Since virtually all benign insulinomas express GLP-1Rs, this should be the imaging modality of choice in cases where conventional morphological imaging fails. No financial support and no other potential conflict of interest relevant to this article was reported.

    JAMA Oncol.