In nuclear medicine, the term
describes the combination of therapy and diagnostic imaging. In practice, this concept dates back more than 50 years; however, among the most successful examples of ...theranostics are peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors. The development of these modalities through the radiolabeling of somatostatin analogs with various radionuclides has led to a revolution in patient management and established a foundation for expansion of the theranostic principle into other oncology indications. This article provides a review of the evolution and development of the theranostic radionuclide approach to the management of neuroendocrine tumors, as described by the inventor of this technique, Eric P. Krenning, in an interview with Rachel Levine.
Peptide receptor radionuclide therapy (PRRT) is a promising new treatment modality for inoperable or metastasized gastroenteropancreatic neuroendocrine tumors patients. Most studies report objective ...response rates in 15% to 35% of patients. Progression-free (PFS) and overall survival (OS) compare favorably with that for somatostatin analogues, chemotherapy, or newer, "targeted" therapies. Prospective, randomized data regarding the potential PFS and OS benefit of PRRT compared with standard therapies is anticipated.
Gastroenteropancreatic neuroendocrine tumours Modlin, Irvin M, Prof; Oberg, Kjell, Prof; Chung, Daniel C, MD ...
The lancet oncology,
2008, 2008-Jan, 2008-01-00, 20080101, Letnik:
9, Številka:
1
Journal Article
Recenzirano
Summary Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical ...syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.
Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic ...disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog (177)Lu-DOTA(0),Tyr(3)octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients.
Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients.
Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis.
Treatment with (177)Lu-DOTA(0),Tyr(3)octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.
Bronchial and gastroenteropancreatic neuroendocrine tumors (NET) are slow-growing tumors, which frequently express somatostatin receptors on their cell membranes. These receptors are targets for ...therapy with Lutetium-177-labeled somatostatin analogues. We have treated over 1,200 patients with peptide receptor radionuclide therapy (PRRT) with
Lu-DOTA
,Tyr
octreotate (
Lu-DOTATATE) since the year 2000 and present the results on efficacy, survival, and toxicity of this therapy.
For safety analysis, 610 patients treated with a cumulative dose of at least 100 mCi (3.7 GBq)
Lu-DOTATATE were included. A subgroup of 443 Dutch patients who were treated with a cumulative dose of at least 600 mCi (22.2 GBq)
Lu-DOTATATE before 2013 was further analyzed for efficacy and survival.
The objective response rate of the total group of patients was 39%. Stable disease was reached in 43% of patients. Progression-free survival (PFS) and overall survival (OS) for all NET patients were 29 months 95% confidence interval (CI), 26-33 months and 63 months (95% CI, 55-72 months). Long-term toxicity included acute leukemia in four patients (0.7%) and myelodysplastic syndrome in nine patients (1.5%). No therapy-related long-term renal or hepatic failure occurred.
PRRT with
Lu-DOTATATE is a favorable therapeutic option in patients with metastatic bronchial and gastroenteropancreatic NETs that express somatostatin receptors. PRRT with
Lu-DOTATATE is safe with few side-effects and shows good response rates with PFS of 29 months and OS of 63 months.
.
We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist
Ga-SB3 (
Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent ...tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu
-Met
-NH
dipeptide of SB3 by Sta
-Leu
-NH
, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting
Ga-,
In-, and
Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using
Ga-NeoBOMB1 and PET/CT is also presented.
NeoBOMB1 was radiolabeled with
Ga,
In, and
Lu according to published protocols. The respective metalated species
Ga-,
In-, and
Lu-NeoBOMB1 were also synthesized and used in competition binding experiments against
I-Tyr
BBN in GRPR-positive PC-3 cell membranes. Internalization of
Ga-,
In-, and
Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a
Ga-,
In-, or
Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr
-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with
Ga-NeoBOMB1 were acquired in prostate cancer patients.
NeoBOMB1 and
Ga-,
In-, and
Lu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1-2 nM).
Ga-,
In-, and
Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (
Ga-,
In-, and
Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients,
Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging.
The GRPR antagonist radioligands
Ga-,
In-, and
Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using
Ga-NeoBOMB1 and PET/CT.
Purpose
Peptide receptor radionuclide therapy (PRRT) with
90
Y and
177
Lu provides objective responses in neuroendocrine tumours, and is well tolerated with moderate toxicity. We aimed to identify ...clinical parameters predictive of long-term renal and haematological toxicity (myelodysplastic syndrome and acute leukaemia).
Methods
Of 807 patients studied at IEO-Milan (1997–2013), 793 (98 %) received
177
Lu (278, 34.4 %),
90
Y (358, 44.4 %) or
177
Lu and
90
Y combined (157. 19.5 %), and 14 (2 %) received combinations of PRRT and other agents. Follow-up was 30 months (1–180 months). The parameters evaluated included renal risk factors, bone marrow toxicity and PRRT features. Data analysis included multiple regression, random forest feature selection, and recursive partitioning and regression trees.
Results
Treatment with
90
Y and
90
Y +
177
Lu was more likely to result in nephrotoxicity than treatment with
177
Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively;
p
< 0.0001). Nephrotoxicity (any grade), transient and persistent, occurred in 279 patients (34.6 %) and was severe (grade 3 + 4) in 12 (1.5 %). In only 20–27 % of any nephrotoxicity was the disease modelled by risk factors and codependent associations (
p
< 0.0001). Hypertension and haemoglobin toxicity were the most relevant factors. Persistent toxicity occurred in 197 patients (24.3 %). In only 22–34 % of affected patients was the disease modelled by the clinical data (
p
< 0.0001). Hypertension (regression coefficient 0.14,
p
< 0.0001) and haemoglobin toxicity (regression coefficient 0.21,
p
< 0.0001) were pertinent factors. Persistent toxicity was associated with shorter PRRT duration from the first to the last cycle (mean 387 vs. 658 days,
p
< 0.004). Myelodysplastic syndrome occurred in 2.35 % of patients (modelled by the clinical data in 30 %,
p
< 0.0001). Platelet toxicity grade (2.05 ± 1.2 vs. 0.58 ± 0.8,
p
< 0.0001) and longer PRRT duration (22.6 ± 24 vs. 15.5 ± 9 months,
p
= 0.01) were relevant. Acute leukaemia occurred in 1.1 % of patients (modelled by the clinical data in 18 %,
p
< 0.0001).
Conclusion
Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry. These data strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease.
Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly ...hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice.
The peptide conjugates DOTA-Ala(1)SS14 (DOTA-Ala-Gly-cCys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH), PanSB1 (DOTA-PEG2-dTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2), and DOTA-MG11 (DOTA-dGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) were labeled with (111)In by 20 min of heating at an acidic pH. Metabolic stability was studied with high-performance liquid chromatography analysis of blood samples collected 5 min after the injection of the test radiopeptide alone or with PA into mice. Biodistribution was studied after injection of each (111)In-labeled radiopeptide alone or after coinjection of PA in tumor-bearing severe combined immunodeficient (SCID) mice.
The amount of intact (111)In-DOTA-Ala(1)SS14 detected in the mouse circulation at 5 min after the injection of PA increased impressively-from less than 2% to 86%-whereas the uptake in AR4-2J xenografts rose from less than 1 percentage injected dose per gram of tissue (%ID/g) to 14 %ID/g at 4 h after injection. Likewise, the coadministration of PA resulted in a marked increase in the amount of circulating intact (111)In-PanSB1-from 12% to 80%-at 5 min after injection, and radioligand uptake in human PC-3 xenografts in SCID mice escalated from less than 4 %ID/g to greater than 21 %ID/g at 4 h after injection. In a similar manner, the coadministration of PA resulted in an equally impressive increase in intact (111)In-DOTAMG11 levels in the mouse bloodstream-from less than 5% to 70%-at 5 min after injection, leading to a remarkable increase in radiotracer uptake-from 2 %ID/g to greater than 15 %ID/g-in both AR4-2J tumors and A431(CCKR+) tumors (i.e., tumors induced by A431 cells transfected to stably express the human cholecystokinin subtype 2 receptor) in mice at 4 h after injection. This effect was well visualized by SPECT/CT imaging of AR4-2J tumor-bearing mice at 4 h after injection.
The results of this study clearly demonstrate that the coadministration of key enzyme inhibitors can effectively prolong the survival of radiolabeled peptides in the circulation, securing their safe transit to the target. This strategy clearly provoked an unprecedented increase in radiolabel accumulation in tumor xenografts in mice; this increase might translate into higher diagnostic sensitivity or improved therapeutic efficacy of radiopeptide drugs in cancer patients. Hence, our findings provide exciting new opportunities for the application of biodegradable (radio)peptide drugs of either natural or synthetic origin as well as for the rationale design of analogs that are stable in vivo.
Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTS1R)-expressing cancer. However, their fast degradation by two major ...peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the ε-amine of Lys7 in 99mTcTc-Lys7DT1 (DT1, N4-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N4 = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized 99mTcTc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice. Aiming to improve the in vivo stability of 99mTcTc-DT1 without compromising pharmacokinetics, we now introduce three new 99mTcTc-DT1 mimics, carrying different pendant groups at the ε-amine of Lys7: MPBA (4-(4-methylphenyl)butyric acid)—99mTcTc-DT10; MPBA via a PEG4-linker—99mTcTc-DT11; or a hydrophilic PEG6 chain—99mTcTc-DT12. The impact of these modifications on receptor affinity and internalization was studied in NTS1R-positive cells. The effects on stability and AsPC-1 tumor uptake were assessed in mice without or during NEP/ACE inhibition. Unlike 99mTcTc-DT10, the longer-chain modified 99mTcTc-DT11 and 99mTcTc-DT12 were significantly stabilized in vivo, resulting in markedly improved tumor uptake compared to 99mTcTc-DT1. 99mTcTc-DT11 was found to achieve the highest AsPC-1 tumor values and good pharmacokinetics, either without or during NEP inhibition, qualifying for further validation in patients with NTS1R-positive tumors using SPECT/CT.
The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for ...theranostic purposes. We have recently shown that
TcTc-DT1 (
TcTc-N
-Gly
NT(7-13)) and
TcTc-DT5 (
TcTc-N
-
Ala
,Dab
NT(7-13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of
TcTc-DT1 and
TcTc-DT5 in pancreatic cancer models.
The cellular uptake of
TcTc-DT1 and
TcTc-DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts.
The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing
TcTc-DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection;
< 0.0001).
This study has shown the feasibility of optimizing the uptake of
TcTc-DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.
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