-
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 -
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 -
Digestion 1996The expression of somatostatin receptors (ssts) on human tumours is the basis for the successful therapeutic and diagnostic application of (radiolabelled) somatostatin... (Review)
Review
The expression of somatostatin receptors (ssts) on human tumours is the basis for the successful therapeutic and diagnostic application of (radiolabelled) somatostatin analogues. Manipulation (up-regulation) of sst expression might improve the uptake of radioligand in in vivo scintigraphy of human sst-positive tumours, as well as the potential success of radiotherapy using radiolabelled SRIF analogues. In colonal pituitary cell lines, agonist exposure (SRIF-14, SRIF-28, octreotide) has been shown to either reduce or increase sst (subtype) expression, suggesting cell-type-specific responsiveness. In addition, glucocorticoids and oestrogens were shown to down- and up-regulate, respectively, sst numbers. So far, little information is available with respect to sst (subtype) regulation in non-pituitary-derived cell types. We have found that sst expression in the model of the transplantable prolactin (PRL)-secreting rat pituitary tumour 7315b is mainly dependent upon the presence of oestradiol (E2), both in vivo and in vitro. This tumour is sst negative in vivo. In vitro, the addition of E2 induces sst expression (sst2 and sst3 subtypes). The in vivo administration of E2 (20 micrograms/day subcutaneously) to 7315b-tumour-bearing rats induces sst2 mRNA expression. The absence of sst expression in 7315b tumours in vivo may be due to the inhibition of ovarian E2 production by the high circulating PRL levels in the 7315b-prolactinoma-bearing rats. Indeed, no detectable E2 levels were found in the serum of 7315b-tumour-bearing rats. Taken together, our data suggest that the 7315b rat prolactinoma can indirectly manipulate (down-regulate) its own sst expression, in vivo, via its host. This experimental 7315b prolactinoma model might be representative for most untreated female prolactinoma patients. Clinically, patients with microprolactinomas do not benefit from octreotide treatment.
Topics: Animals; Female; Hormone Antagonists; Humans; Pituitary Neoplasms; Prolactinoma; Rats; Receptors, Somatostatin; Somatostatin
PubMed: 8813458
DOI: 10.1159/000201383 -
Pituitary Feb 2017First-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these... (Review)
Review
First-generation somatostatin receptors ligands (SRL) are the mainstay in the medical treatment of acromegaly, however the percentage of patients controlled with these drugs significantly varies in the different studies. Many factors are involved in the resistance to SRL. In this review, we update the physiology of somatostatin and its receptors (sst), the use of SRL in the treatment of acromegaly and the factors involved in the response to these drugs. The SRL act through interaction with the sst, which up to now have been characterized as five subtypes. The first-generation SRL, octreotide and lanreotide, are considered sst2 specific and have biochemical response rates varying from 20 to 70%. Tumor volume reduction can be found in 36-75% of patients. Several factors may determine the response to these drugs, such as sst, AIP, E-cadherin, ZAC1, filamin A and β-arrestin expression in the somatotropinomas. In patients resistant to first-generation SRL, alternative medical treatment options include: SRL high dose regimens, SRL in combination with cabergoline or pegvisomant, or the use of pasireotide. Pasireotide is a next-generation SRL with a broader pattern of interaction with sst. In the light of the recent increase of treatment options in acromegaly and the deeper knowledge of the determinants of response to the current first-line therapy, a shift from a trial-and-error treatment to a personalized one could be possible.
Topics: Acromegaly; Humans; Octreotide; Peptides, Cyclic; Receptors, Somatostatin; Somatostatin
PubMed: 28176162
DOI: 10.1007/s11102-017-0791-0 -
World Neurosurgery May 2021Fluorescence-guided surgery may improve completeness of resection in transsphenoidal surgery for Cushing disease (CD) by enabling visualization of residual tumor tissue... (Review)
Review
OBJECTIVES
Fluorescence-guided surgery may improve completeness of resection in transsphenoidal surgery for Cushing disease (CD) by enabling visualization of residual tumor tissue at the margins. In this review we discuss somatostatin receptors (SSTRs) as targets for fluorescence-guided surgery and overview existing SSTR-specific imaging agents. We also compare SSTR expression in normal pituitary and corticotrophinoma tissues from human and canine CD patients to assess canines as a translational model for CD.
METHODS
A PubMed literature search was conducted for publications containing the terms canine, somatostatin receptor, Cushing's disease, and corticotroph adenoma. SSTR expression data from each study was documented as the presence or absence of expression or, when possible, the number of tumors expressing a given SSTR subtype within a group of tumors being studied. Studies that used reverse transcription polymerase chain reaction to quantify SSTR expression were selected for additional comparative analysis.
RESULTS
SSTR5 is strongly expressed in human corticotroph adenomas and weakly expressed in surrounding pituitary parenchyma, a pattern not conclusively observed in canine patients. SSTR2 mRNA expression is similar in human normal pituitary and corticotrophinoma cells but may be significantly higher in canine normal pituitary tissue than in corticotroph tumoral tissue. Limited data were available on SSTR subtypes 1, 3, and 4.
CONCLUSIONS
Further studies must fill the knowledge gaps related to species-specific SSTR expression, so using canine CD as a translational model may be premature. We do conclude that the expression profile of SSTR5 (i.e., high local expression in pituitary adenomas relative to normal surrounding tissues) makes SSTR5 a promising molecular target for FGS.
Topics: Animals; Dogs; Humans; Molecular Imaging; Pituitary ACTH Hypersecretion; Receptors, Somatostatin; Species Specificity
PubMed: 33601082
DOI: 10.1016/j.wneu.2021.02.034 -
Journal of Endocrinological... Nov 2020Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor... (Review)
Review
BACKGROUND
Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST and SST are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST and SST. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors.
METHODS
Critical revision of literature data correlating SST expression with patients' response to SRLs.
RESULTS
SST expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST expression, pasireotide can act throughout SST. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST expression observed in nearly 100% of cases, as well as to the balanced amount of SST. In corticotroph tumors, pasireotide mainly act via SST, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype.
CONCLUSIONS
The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.
Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Gene Expression Regulation, Neoplastic; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Molecular Targeted Therapy; Octreotide; Pituitary Neoplasms; Receptors, Somatostatin; Somatostatin
PubMed: 32557353
DOI: 10.1007/s40618-020-01335-0 -
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 -
Nuclear Medicine Review. Central &... 2016The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in... (Review)
Review
The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1-octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin were constructed aiming at their agonistic behavior, expecting that their internalization with the receptor acti-vated by the radiolabeled ligand and its retention within the tumor cell are crucial for efficient imaging and therapy. Recently it has been shown that the antagonists recognize more binding sites at the tumor cell membrane and hence offer an improved diagnostic efficacy, especially when the density of sst receptors is low. This approach may in future improve diagnostic value of somatostatin receptor imaging techniques. The developments in tracer design are followed by the improvements in imaging techniques. The new SPECT scanners offer resolution close to that of PET, which might open a new era for 99mTc and other SPECT radiotracers.
Topics: Drug Stability; Humans; Molecular Imaging; Neuroendocrine Tumors; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin
PubMed: 27479790
DOI: 10.5603/NMR.2016.0024 -
Trends in Endocrinology and Metabolism:... Mar 2010Somatotropin-release inhibitory factor (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell... (Review)
Review
Somatotropin-release inhibitory factor (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell growth. Five SRIF receptor subtypes (SSTR1-5) are ubiquitously expressed G-protein coupled receptors. In the pituitary, SSTR1, 2, 3 and 5 are expressed, with SSTR2 and SSTR5 predominating. As new SRIF analogs have recently been introduced for treatment of pituitary disease, we evaluate the current knowledge of cell-specific pituitary SRIF receptor signaling and highlight areas of future research for comprehensive understanding of these mechanisms. Elucidating pituitary SRIF receptor signaling enables understanding of pituitary hormone secretion and cell growth, and also encourages future therapeutic development for pituitary disorders.
Topics: Animals; Humans; Models, Biological; Pituitary Diseases; Pituitary Hormones; Receptors, Somatostatin; Signal Transduction
PubMed: 20149677
DOI: 10.1016/j.tem.2009.12.003 -
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