To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ((90)Y-DOTA-TOC) in ...neuroendocrine cancers.
In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of (90)Y-DOTA-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface (90)Y-DOTA-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity.
Overall, 1,109 patients received 2,472 cycles of (90)Y-DOTA-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio HR, 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003).
This study documents the long-term outcome of (90)Y-DOTA-TOC treatment in a large cohort. Response to (90)Y-DOTA-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after (90)Y-DOTA-TOC treatment and occurrence of renal toxicity.
We aimed to explore the efficacy of (90)Yttrium-1,4,7,10-tetra-azacyclododecane N,N',N'',N-'''-tetraacetic acid ((90)Y-DOTA)-Tyr(3)-octreotide (TOC) therapy in advanced medullary thyroid cancer.
In a ...phase II trial, we investigated the response, survival, and long-term safety profile of systemic (90)Y-DOTA-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models.
Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of (90)Y-DOTA-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidence interval, 0.05-0.81; P = 0.02) and from time of first (90)Y-DOTA-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009). The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival.
Response to (90)Y-DOTA-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.
Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While ...agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists NH₂-CO-c(DCys-Phe-Tyr-DAgI⁸(Me,2-naphthoyl)-Lys-ThrPhe-Cys)-OH (sst₃-ODN-8) and a sst₂-selective antagonist (sst₂-ANT), for labeling with$^{1ll/nat}ln$.$^{111/nat}ln-DOTA-sst_{3}-ODN-8$and$^{111/nat}lnDOTA-4-NO_{2}-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH_{2} (^{1ll/nat}lnDOTA-sst_{2}-ANT)$showed high sst₃- and sst₂-binding affinity, respectively. They did not trigger sst₃ or sst₂ internalization but prevented agonist-stimulated internalization.$^{111}ln-DOTA-sst_{3}ODN-8$and$^{111}1n-DOTA-sst_{2}-ANT$were injected intravenously into mice bearing sst₃- and sst₂-expressing tumors, and their biodistribution was monitored. In the sst₃-expressing tumors, strong accumulation of$^{111}ln-DOTA-sst_{3}-ODN-8$was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst₃-ODN-8 blocked uptake. As a control, the potent agonist$^{111}1n-DOTA-1-Nal^{3}-octreotide$, with strong sst₃-binding and internalization properties showed a much lower and shorter-lasting uptake in sst3-expressing tumors. Similarly,$^{111}1n-DOTA-sst_{2}-ANT$was injected into mice bearing sst₂expressing tumors. Tumor uptake was considerably higher than with the highly potent sst₂-selective agonist$^{111}1n-diethylenetriaminepentaacetic$acid-Tyr,Thr⁸-octreotide ($^{111}1n-DTPA-TATE$). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst₃- or sst₂-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.
Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of ...radioisotopes.
In a cohort study, patients with metastasized neuroendocrine cancer were treated with repeated cycles of (90)yttrium-labeled tetraazacyclododecane-tetraacetic acid modified Tyr-octreotide ((90)Y-DOTA-TOC) or with cycles alternating between (90)Y-DOTA-TOC and (177)lutetium-labeled DOTA-TOC ((177)Lu-DOTA-TOC) until tumor progression or permanent toxicity. Multivariable Cox regression and competing risk regression were used to study predictors of survival and renal toxicity in patients completing three or more treatment cycles.
A total of 486 patients completed three or more treatment cycles; 237 patients received (90)Y-DOTA-TOC and 249 patients received (90)Y-DOTA-TOC + (177)Lu-DOTA-TOC. Patients receiving (90)Y-DOTA-TOC + (177)Lu-DOTA-TOC had a significantly longer survival than patients receiving (90)Y-DOTA-TOC alone (5.51 v 3.96 years; hazard ratio, 0.64; 95% CI, 0.47 to 0.88; P = .006). The rates of severe hematologic toxicities (6.3% v 4.4%; P = .25) and severe renal toxicity (8.9% v 11.2%; P = .47) were comparable in both groups.
(90)Y-DOTA-TOC + (177)Lu-DOTA-TOC was associated with improved overall survival compared with (90)Y-DOTA-TOC alone in patients completing three or more cycles of treatment. Contrary to the current practice in radiopeptide therapy, our results suggest an advantage of using a combination of radioisotopes.
Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We ...have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of Lys(40)(Ahx-DTPA-(111)In)NH(2)-Exendin-4, an (111)In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.
Lys(40)(Ahx-DTPA-(111)In)NH(2)-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated.
Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol Lys(40)(Ahx-DTPA-(111)In)NH(2)-Exendin-4. Other GLP-1R-positive organs showed > or =30 times lower dose deposition. A single injection of Lys(40)(Ahx-DTPA-(111)In)NH(2)-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation.
The results suggest that Lys(40)(Ahx-DTPA-(111)In)NH(2)-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as (111)In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.
Somatostatin analogs that activate the somatostatin subtype 2A (sst2A) receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable ...of activating multiple somatostatin receptor subtypes have been developed to increase tumor responsiveness. We tested two such multi-somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells, somatostatin inhibited cAMP production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells; pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin's actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.
Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT ...using Lys(40)(Ahx 6-aminohexanoic acid-DOTA-(111)In)NH(2)-exendin-4 can localize hardly detectable insulinomas. However, Lys(40)(Ahx-DOTA-(111)In)NH(2)-exendin-4 imaging has drawbacks related to the use of (111)In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of Lys(40)(Ahx-DOTA-(68)Ga)NH(2)-exendin-4 for PET/CT and Lys(40)(Ahx-hydrazinonicotinamide HYNIC-(99m)Tc)NH(2)-exendin-4 for SPECT/CT.
Internalization, biodistribution, dosimetry, and imaging studies were performed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis and compared with our gold standard Lys(40)(Ahx-DOTA-(111)In)NH(2)-exendin-4. Poly-glutamic acid and Gelofusine, a gelatin-based plasma expander, were used for renal uptake reduction studies.
The tumor uptake of Lys(40)(Ahx-DOTA-(68)Ga)NH(2)-exendin-4 was 205 +/- 59 percentage injected activity per gram of tissue at 4 h. Other GLP-1 receptor-positive organs showed more than 4.8 times lower radioactivity uptake. Lys(40)(Ahx-HYNIC-(99m)Tc/ethylenediaminediacetic acid EDDA)NH(2)-exendin-4, compared with its (111)In- and (68)Ga-labeled sister compounds, showed significantly less tumor and organ uptake. The significantly lower tumor and organ uptake of Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%-78% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 muSv/MBq for Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)-exendin-4, which was 8 times less than that for Lys(40)(Ahx-DOTA-(68)Ga)NH(2)-exendin-4 and 43 times less than that for Lys(40)(Ahx-DOTA-(111)In)NH(2)-exendin-4.
These promising pharmacokinetic and imaging data show that Lys(40)(Ahx-DOTA-(68)Ga)NH(2)-exendin-4 and Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)-exendin-4 are suitable candidates for clinical GLP-1 receptor imaging studies.
Gastrin releasing peptide (GRP) is a regulatory peptide that acts through its receptor (GRPR) to regulate physiological functions in various organs. GRPR is overexpressed in neoplastic cells of most ...prostate cancers and some renal cell cancers and in the tumoral vessels of urinary tract cancers. Thus, targeting these tumours with specifically designed GRP analogues has potential clinical application. Potent and specific radioactive, cytotoxic or nonradioactive GRP analogues have been designed and tested in various animal tumour models with the aim of receptor targeting for tumour diagnosis or therapy. All three categories of compound were found suitable for tumour targeting in animal models. The cytotoxic and nonradioactive GRP analogues have not yet shown convincing tumour-reducing effects in human trials; however, the first clinical studies of radioactive GRP analogues--both agonists and antagonists--suggest promising opportunities for both diagnostic tumour imaging and radiotherapy of prostate and other GRPR-expressing cancers.
High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using ...receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor targeting and to use a newly designed exendin-4-DTPA (DTPA is diethylenetriaminepentaacetic acid) conjugate for GLP-1 receptor targeting.
Exendin-4 was modified C-terminally with Lys(40)-NH(2), whereby the lysine side chain was conjugated with Ahx-DTPA (Ahx is aminohexanoic acid). The GLP-1 receptor affinity (50% inhibitory concentration IC(50) value) of Lys(40)(Ahx-DTPA)NH(2)exendin-4 as well as the GLP-1 receptor density in tumors and different organs of Rip1Tag2 mice were determined. Rip1Tag2 mice are transgenic mice that develop insulinomas in a well-defined multistage tumorigenesis pathway. This animal model was used for biodistribution studies, pinhole SPECT/MRI, and SPECT/CT. Peptide stability, internalization, and efflux studies were performed in cultured beta-tumor cells established from tumors of Rip1Tag2 mice.
The GLP-1 receptor affinity of Lys(40)(Ahx-DTPA)NH(2)exendin-4 was found to be 2.1 +/- 1.1 nmol/L (mean +/- SEM). Because the GLP-1 receptor density in tumors of Rip1Tag2 mice was very high, a remarkably high tumor uptake of 287 +/- 62 %IA/g (% injected activity per gram tissue) was found 4 h after injection. This resulted in excellent tumor visualization by pinhole SPECT/MRI and SPECT/CT. In accordance with in vitro data, Lys(40)(Ahx-DTPA-(111)In)NH(2)exendin-4 uptake in Rip1Tag2 mice was also found in nonneoplastic tissues such as pancreas and lung. However, lung and pancreas uptake was distinctly lower compared with that of tumors, resulting in a tumor-to-pancreas ratio of 13.6 and in a tumor-to-lung ratio of 4.4 at 4 h after injection. Furthermore, in vitro studies in cultured beta-tumor cells demonstrated a specific internalization of Lys(40)(Ahx-DTPA-(111)In)NH(2)exendin-4, whereas peptide stability studies indicated a high metabolic stability of the radiopeptide in beta-tumor cells and human blood serum.
The high density of GLP-1 receptors in insulinomas as well as the high specific uptake of Lys(40)(Ahx-DTPA-(111)In)NH(2)exendin-4 in the tumor of Rip1Tag2 mice indicate that targeting of GLP-1 receptors in insulinomas may become a useful imaging method to localize insulinomas in patients, either preoperatively or intraoperatively. In addition, Rip1Tag2 transgenic mice represent a suitable animal tumor model for GLP-1 receptor targeting.
In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin ...radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-Tyr3-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-Tyr3-octreotate and DOTA-Tyr3-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-Tyr3-octreotide (IC50 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-Tyr3-octreotate (IC50 1.3 nM) and for Y-DOTA-Tyr3-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-Tyr3-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr3-containing analogue, suggesting that replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-Tyr3-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either Tyr3-octreotide or Tyr3-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands.
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