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-cd-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.
Purpose
Benign insulinomas are the most prevalent cause of endogenous hyperinsulinaemic hypoglycaemia (EHH) in adults, and because of their small size are difficult to localise. The purpose of the ...study was to test the diagnostic accuracy and clinical impact of glucagon-like peptide-1 receptor (GLP-1R) PET/CT using
68
Ga-DOTA-exendin-4 in consecutive adult patients referred for localisation of insulinomas. The results were compared with
111
In-DOTA-exendin-4 SPECT/CT, study-MRI and previously performed external CT and/or MRI (prior external CT/MRI).
Methods
We prospectively enrolled patients with neuroglycopenic symptoms due to EHH. GLP-1R PET/CT, SPECT/CT and study-MRI were performed in a randomised, crossover order within 3–4 days. The reference standard was surgery with histology and treatment outcome.
Results
From January 2014 until March 2017, 52 patients were recruited. All imaging and invasive procedures before recruitment identified suspicious lesions in 46.2% of patients. GLP-1R PET/CT, SPECT/CT and study-MRI detected suspicious lesions in 78.8%, 63.5% and 63.4% of patients, respectively. In 38 patients, conclusive histology was available for final analysis.
Accuracy (95% confidence interval) for PET/CT, SPECT/CT, study-MRI and prior external CT/MRI was 93.9% (87.8–97.5%), 67.5% (58.1–76.0%), 67.6% (58.0–76.1%) and 40.0% (23.9–57.9%), respectively (all
P
values < 0.01, except comparison of SPECT/CT and study-MRI with a
P
value = 1.0). Impact on clinical management was 42.3%, 32.7% and 33.3% for PET/CT, SPECT/CT and study-MRI, respectively. Percentage reading agreement was 89.5%, 75.7%, and 71.1% for PET/CT, SPECT/CT and study-MRI, respectively.
Conclusion
68
Ga-DOTA-exendin-4 PET/CT performed significantly better than
111
In-DOTA-exendin-4 SPECT/CT and MRI in the localisation of benign insulinomas and should be considered in patients where localisation fails with CT/MRI (
ClinicalTrials.gov
, NCT02127541).
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumors, mainly localized in the gastrointestinal system. What characterizes NENs is the expression of hormone receptors on the tumor ...cell surface, making them accessible for diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides. Somatostatin receptors subtype-two (SST2) play an important role in NENs since they are overexpressed and homogeneously distributed at the surface of the majority of NENs. Accordingly, targeting SST2 for diagnostic and therapeutic purposes has been established. Current research aims at upregulating its expression by epigenetic treatment or improving its targeting via use of alternative radioligands. In addition, recent data suggest a future role of SST antagonists as a diagnostic tool and a potential therapeutic option. Another promising target is the glucagon-like peptide-1 (GLP-1) receptor. Targeting GLP-1R using exendin-4 (GLP-1 analogue) has a high sensitivity for the localization of the often SST2-negative sporadic insulinomas and insulinomas in the context of multiple endocrine neoplasia type-1. Further options for patients with insufficient expression of SST2 involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4), which have been evaluated for potential theranostic approach in symptomatic NENs or dedifferentiated tumors. Recently, new targets such as the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs. Finally, minigastrin – a ligand targeting the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut neuroendocrine tumors – may improve future management of these diseases with currently limited therapeutic options. This review summarises the current approaches and future challenges of diagnostic and therapeutic evaluations in neuroendocrine neoplasms.
Radiolabeled somatostatin receptor (sstr) antagonists have shown superiority in different preclinical and clinical settings compared with the well‐established and clinically used agonists for ...targeting sstr‐expressing tumors, with regard to pharmacokinetics, tumor uptake, and retention. The theranostic pair 177Lu‐OPS201/68Ga‐OPS202, based on the sstr2 antagonist JR11 (Cpa‐cd‐Cys‐Aph(Hor)‐d‐Aph(Cbm)‐Lys‐Thr‐Cys‐d‐Tyr‐NH2), is the most advanced pair of the antagonist family in terms of preclinical development and is currently under clinical evaluation. OPS201 and OPS202 share the same amino acid sequence (JR11) but feature different conjugated chelators needed for radiolabeling, DOTA for OPS201 and NODAGA for OPS202. In this review, the design and development of the peptidic analog, JR11, and the selection of chelators and radiometals that led to 177Lu‐OPS201/68Ga‐OPS202 are discussed. Furthermore, the preclinical evaluation of both radiolabeled analogs from bench to bedside and the clinical trials involving the theranostic pair are presented.
Targeting somatostatin receptor (sstr) expressing tumors with radiolabeled sstr agonists is established for diagnosis and treatment of neuroendocrine tumors. There is now evidence for improved diagnostic sensitivity and therapeutic efficacy when shifting to sstr antagonists. 177Lu‐OPS201 (177Lu‐DOTA‐JR11) and 68Ga‐OPS202 (68Ga‐NODAGA‐JR11) is the most advanced theranostic pair of the antagonist family. This review discusses 177Lu‐OPS201/68Ga‐OPS202 from bench to bedside.
Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST
) being the predominantly and most ...frequently expressed. PET/CT imaging with
Ga-labeled SST agonists, e.g.,
Ga-DOTA-TOC (SomaKit TOC
) or
Ga-DOTA-TATE (NETSPOT
), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts
Lu-DOTA-TOC or
Lu-DOTA-TATE (Lutathera
). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST
antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic α-emitters, such as
Ac, or β
and Auger electrons, such as
Tb, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with β
-emitters.
Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST
) peptide agonist
LuLu-DOTA-TATE is effective and well-established. Recent studies suggest improved ...therapeutic efficacy using the SST
peptide antagonist
LuLu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of
LuLu-OPS201 versus
LuLu-DOTA-TATE using HEK cells stably transfected with the human SST
. While
LuLu-OPS201 and
LuLu-DOTA-TATE exhibited comparable affinity (K
, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively),
LuLu-OPS201 recognized four times more binding sites than
LuLu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of
LuLu-OPS201 bound to HEK-SST
cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist.
LuLu-OPS201 showed faster association and slower dissociation than
LuLu-DOTA-TATE. Whereas most of
LuLu-OPS201 remained at the cell surface,
LuLu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between
LuLu-OPS201 and
LuLu-DOTA-TATE regarding the recognition of receptor binding sites (higher for
LuLu-OPS201) and their kinetics (faster association and slower dissociation of
LuLu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of
LuLu-OPS201 compared to
LuLu-DOTA-TATE.
Fibroblast activation protein α (FAP) plays an important role in tissue remodeling and helps tumor cells invade surrounding tissue. We sought to investigate FAP as a prognostic molecular marker in ...colorectal cancer (CRC) using immunohistochemical and transcriptomic data.
expression and clinicopathological information were obtained from The Cancer Genome Atlas data set. The association of
expression and tissue cellular heterogeneity landscape was explored using the xCell method. We evaluated FAP protein expression in a cohort of 92 CRCs and 19 non-tumoral tissues. We observed that
was upregulated in tumors both at the mRNA and protein levels, and its expression was associated with advanced stages, poor survival, and consensus molecular subtype 4.
expression was also associated with angiogenesis and collagen degradation. We observed an enrichment in immune-cell process-related genes associated with
overexpression. Colorectal cancers with high
expression display an inflamed phenotype enriched for macrophages and monocytes. Those tumors showed enrichment for regulatory T cell populations and depletion of T
1 and natural killer T cells, pointing to an immunosuppressive environment. Colorectal cancers with high levels of stromal FAP are associated with aggressive disease progression and survival. Our results suggest that FAP plays additional roles in tumor progression such as modulation of angiogenesis and immunoregulation in the tumor microenvironment.
Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced ...radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, ...such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery.
To evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI.
Post hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH.
Six of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included.
All patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results.
Lesion-based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs ≥20 mm or insulinoma.
In six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients.
68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and may guide the surgical strategy.
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