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Zhang S, Wang X, Gao X, Chen X, Li L, Li G, Liu C, Miao Y, Wang R, Hu K. Radiopharmaceuticals and their applications in medicine. Signal Transduct Target Ther 2025; 10:1. [PMID: 39747850 PMCID: PMC11697352 DOI: 10.1038/s41392-024-02041-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/30/2024] [Accepted: 10/28/2024] [Indexed: 01/04/2025] Open
Abstract
Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases. Radiopharmaceutical therapy, which directly causes systematic and irreparable damage to targeted cells, has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies. As the Food and Drug Administration (FDA) approvals of [177Lu]Lu-DOTA-TATE, [177Lu]Lu-PSMA-617 and their complementary diagnostic agents, namely, [68Ga]Ga-DOTA-TATE and [68Ga]Ga-PSMA-11, targeted radiopharmaceutical-based theranostics (radiotheranostics) are being increasingly implemented in clinical practice in oncology, which lead to a new era of radiopharmaceuticals. The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition, making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy. Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets, demonstrating remarkable in vivo performance. These include high tumor uptake, prolonged retention time, and favorable pharmacokinetic properties that align with clinical standards. While radiotheranostics have been widely applied in tumor diagnosis and therapy, their applications are now expanding to neurodegenerative diseases, cardiovascular diseases, and inflammation. Furthermore, radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm. Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning, leading to improved therapeutic outcomes in targeted radionuclide therapy. This review offers a comprehensive overview of the evolution of radiopharmaceuticals, including both FDA-approved and clinically investigated agents, and explores the mechanisms of cell death induced by radiopharmaceuticals. It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.
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Grants
- 82372002 National Natural Science Foundation of China (National Science Foundation of China)
- 0104002 Beijing Nova Program
- L248087; L234044 Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)
- Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (No. 2022-RC350-04), the CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-026, 2022-I2M-2-002-2, and 2021-I2M-3-001), the National Key Research and Development Program of China (No. 2022YFE0111700),the Fundamental Research Funds for the Central Universities (Nos. 3332023044 and 3332023151), the CIRP Open Fund of Radiation Protection Laboratories (No. ZHYLYB2021005), and the China National Nuclear Corporation Young Talent Program.
- Fundamental Research Funds for the Central Universities,Nos. 3332023044
- Fundamental Research Funds for the Central Universities,Nos. 3332023151
- he Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-RC350-04;the CAMS Innovation Fund for Medical Sciences,Nos. 2021-I2M-1-026, 2022-I2M-2-002-2, and 2021-I2M-3-001;the National Key Research and Development Program of China,No. 2022YFE0111700
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Affiliation(s)
- Siqi Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xingkai Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xin Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Xueyao Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Linger Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Guoqing Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Can Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Yuan Miao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China
| | - Rui Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China.
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Lanzhou University, 2019RU066, 730000, Lanzhou, China.
| | - Kuan Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 100050, Beijing, China.
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Miller C, Klyuzhin I, Chaussé G, Brosch-Lenz J, Koniar H, Shi K, Rahmim A, Uribe C. Impact of cell geometry, cellular uptake region, and tumour morphology on 225Ac and 177Lu dose distributions in prostate cancer. EJNMMI Phys 2024; 11:97. [PMID: 39570450 PMCID: PMC11582247 DOI: 10.1186/s40658-024-00700-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/06/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Radiopharmaceutical therapy with 225Ac- and 177Lu-PSMA has shown promising results for the treatment of prostate cancer. However, the distinct physical properties of alpha and beta radiation elicit varying cellular responses, which could be influenced by factors such as tumour morphology. In this study, we use simulations to examine how cell geometry, region of pharmaceutical uptake within the cell to model different internalization fractions, and the presence of tumour hypoxia and necrosis impact nucleus absorbed doses and dose heterogeneity with 225Ac and 177Lu. We also develop nucleus absorbed dose kernels for application to autoradiography images. METHODS We used the GATE Monte Carlo software to simulate three geometries of LNCaP prostate cancer cells (spherical, cubic, and ovoid) with activity of 225Ac or 177Lu internalized in the cytoplasm or bound to the extracellular membrane. Nucleus S-values were calculated for each geometry, source region, and isotope. The cell models were used to create nucleus absorbed dose kernels for each source region describing the dose to each nucleus in a cell layer, which were applied to simulated tumours composed of normoxic, hypoxic, or necrotic cancer cells to obtain dose rate maps. Absorbed doses within the tumours and dose heterogeneity were analyzed for each tumour morphology and isotope. Cell geometry made a minimal impact on S-values to the nucleus, however internalization resulted in higher nucleus doses. Applying the kernels to the simulated tumour maps showed that doses to each cell type varied between 225Ac and 177Lu depending on tumour morphology. Dose heterogeneity within tumours was slightly higher with 225Ac, however the tumour morphology made a larger impact on dose heterogeneity compared to the choice of isotope, with hypoxic and necrotic tumours having very heterogeneous dose distributions. CONCLUSIONS Cell geometry simplifications may still allow robust results in simulation studies. Furthermore, the morphology of the tumour itself may make a larger impact on treatment response compared to other variables such as ratio of internalization. Finally, nucleus absorbed dose kernels were created that could enable microdosimetric studies with autoradiography.
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Affiliation(s)
- Cassandra Miller
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Physics, University of British Columbia, Vancouver, BC, Canada
| | - Ivan Klyuzhin
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | | | - Julia Brosch-Lenz
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
| | - Helena Koniar
- Department of Physics, University of British Columbia, Vancouver, BC, Canada
| | - Kuangyu Shi
- Department of Nuclear Medicine, Bern University Hospital, The University of Bern, Bern, Switzerland
| | - Arman Rahmim
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada
- Department of Physics, University of British Columbia, Vancouver, BC, Canada
- Department of Radiology, University of British Columbia, Vancouver, BC, Canada
| | - Carlos Uribe
- Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
- Department of Radiology, University of British Columbia, Vancouver, BC, Canada.
- Molecular Imaging and Therapy, BC Cancer Research Institute, Vancouver, BC, Canada.
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Busslinger SD, Mapanao AK, Kegler K, Bernhardt P, Flühmann F, Fricke J, Zeevaart JR, Köster U, van der Meulen NP, Schibli R, Müller C. Comparison of the tolerability of 161Tb- and 177Lu-labeled somatostatin analogues in the preclinical setting. Eur J Nucl Med Mol Imaging 2024; 51:4049-4061. [PMID: 39046521 PMCID: PMC11527941 DOI: 10.1007/s00259-024-06827-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/30/2024] [Indexed: 07/25/2024]
Abstract
PURPOSE [177Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [177Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [161Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of 161Tb- and 177Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice. METHODS Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [161Tb]Tb-DOTA-LM3 or [161Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the 177Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study. RESULTS The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [161Tb]Tb-DOTA-LM3 or [161Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the 161Tb- and 177Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30-50% and 6-12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities. CONCLUSION Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [161Tb]Tb-DOTA-LM3 and [161Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective 177Lu-based analogues.
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Affiliation(s)
- Sarah D Busslinger
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
| | - Ana Katrina Mapanao
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
| | | | - Peter Bernhardt
- Department of Medical Radiation Sciences, Institution of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41345, Sweden
- Department of Medical Physics and Biomedical Engineering (MFT), Sahlgrenska University Hospital, Gothenburg, 41345, Sweden
| | - Fabienne Flühmann
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
| | - Julia Fricke
- Division of Nuclear Medicine, University Hospital Basel, Basel, 4031, Switzerland
| | - Jan Rijn Zeevaart
- Radiochemistry, South African Nuclear Energy Corporation (Necsa), Brits, 0240, South Africa
| | - Ulli Köster
- Institut Laue-Langevin, Grenoble, 38042, France
| | - Nicholas P van der Meulen
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
- Laboratory of Radiochemistry, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland
- Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Cristina Müller
- Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland.
- Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland.
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Cheng J, Zink J, O'Neill E, Cornelissen B, Nonnekens J, Livieratos L, Terry SYA. Enhancing [ 177Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with metronomic chemotherapeutics. EJNMMI Res 2024; 14:73. [PMID: 39136880 PMCID: PMC11322472 DOI: 10.1186/s13550-024-01135-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/29/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE. RESULTS Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7-1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively. CONCLUSIONS Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE.
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Affiliation(s)
- Jordan Cheng
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
| | - Joke Zink
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Edward O'Neill
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Bart Cornelissen
- Department of Nuclear Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Oncology, University of Oxford, Oxford, UK
| | - Julie Nonnekens
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Lefteris Livieratos
- Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
- Department of Nuclear Medicine, Guy's & St Thomas' Hospitals NHS Foundation Trust, London, SE1 7EH, UK
| | - Samantha Y A Terry
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK.
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Waked A, Crabbé M, Neirinckx V, Pérez SR, Wellens J, Rogister B, Benotmane MA, Vermeulen K. Preclinical evaluation of CXCR4 peptides for targeted radionuclide therapy in glioblastoma. EJNMMI Radiopharm Chem 2024; 9:52. [PMID: 39008219 PMCID: PMC11250742 DOI: 10.1186/s41181-024-00282-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Glioblastoma (GBM), is the most fatal form of brain cancer, with a high tendency for recurrence despite combined treatments including surgery, radiotherapy, and chemotherapy with temozolomide. The C-X-C chemokine receptor 4 (CXCR4) plays an important role in tumour radioresistance and recurrence, and is considered as an interesting GBM target. TRT holds untapped potential for GBM treatment, with CXCR4-TRT being a promising strategy for recurrent GBM treatment. Our study focuses on the preclinical assessment of different 177Lu-labelled CXCR4-targeting peptides, CTCE-9908, DV1-K-DV3, and POL3026 for GBM treatment and exploring some of the radiobiological mechanisms underlying these therapies. RESULTS All three DOTA-conjugated peptides could be radiolabelled with 177Lu with > 95% radiochemical yield. Binding studies show high specific binding of [177Lu]Lu-DOTA-POL3026 to U87-CXCR4 + cells, with 42% of the added activity binding to the membrane at 1 nM, and 6.5% internalised into the cells. In the presence of the heterologous CXCR4 blocking agent, AMD11070, membrane binding was reduced by 95%, a result confirmed by quantitative in vitro autoradiography of orthotopic GBM xenograft sections. An activity-dependent decrease in cell viability was observed for [177Lu]Lu-DOTA-DV1-K-DV3 and [177Lu]Lu-DOTA-POL3026, along with a slight increase in the induction of apoptotic markers. Additionally, the expression of γH2AX increased in a time-and activity-dependent manner. Ex vivo biodistribution studies with [177Lu]Lu-DOTA-POL3026 show uptake in the tumour reaching a SUV of 1.9 at 24 h post-injection, with higher uptake in the kidneys, lungs, spleen, and liver. Dosimetry estimations show an absorbed dose of 0.93 Gy/MBq in the tumour. A blocking study with AMD11070 showed a 38% reduction in tumour uptake, with no significant reduction observed in µSPECT imaging. Although no brain uptake was observed in the ex vivo biodistribution study, autoradiography on U87-CXCR4 + tumour inoculated mouse brain slices shows non-specific binding in the brain, next to high specific binding to the tumour. CONCLUSIONS In conclusion, we compared different 177Lu-radiolabelled CXCR4-targeting peptides for their binding potential in GBM, and demonstrated their varied cytotoxic action against GBM cells in vitro, with POL3026 being the most promising, causing considerable DNA damage. Though the peptide's systemic biodistribution remains to be improved, our data demonstrate the potential of [177Lu]Lu-DOTA-POL3026 for CXCR4-TRT in the context of GBM.
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Affiliation(s)
- Anthony Waked
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
- Laboratory of Nervous System Disorders and Therapy, GIGA Neurosciences, Université de Liège, Liège, Belgium
| | - Melissa Crabbé
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Virginie Neirinckx
- Laboratory of Nervous System Disorders and Therapy, GIGA Neurosciences, Université de Liège, Liège, Belgium
| | - Sunay Rodriguez Pérez
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Jasmien Wellens
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Bernard Rogister
- Laboratory of Nervous System Disorders and Therapy, GIGA Neurosciences, Université de Liège, Liège, Belgium
- Neurology Department, CHU de Liège, Liège, Belgium
| | - M Abderrafi Benotmane
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Koen Vermeulen
- Nuclear Medical Applications Institute, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium.
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Santo G, Di Santo G, Virgolini I. Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: Agonist, Antagonist and Alternatives. Semin Nucl Med 2024; 54:557-569. [PMID: 38490913 DOI: 10.1053/j.semnuclmed.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/14/2024] [Accepted: 02/14/2024] [Indexed: 03/17/2024]
Abstract
Peptide receptor radionuclide therapy (PRRT) today is a well-established treatment strategy for patients with neuroendocrine tumors (NET). First performed already more than 30 years ago, PRRT was incorporated only in recent years into the major oncology guidelines, based on its proven efficacy and safety in clinical trials. Following the phase 3 NETTER-1 trial, which led to the final registration of the radiopharmaceutical Luthatera® for G1/G2 NET patients in 2017, the long-term results of the phase 3 NETTER-2 trial may pave the way for a new treatment option also for advanced G2/G3 patients as first-line therapy. The growing knowledge about the synergistic effect of combined therapies could also allow alternative (re)treatment options for NET patients, in order to create a tailored treatment strategy. The evolving thera(g)nostic concept could be applied for the identification of patients who might benefit from different image-guided treatment strategies. In this scenario, the use of dual tracer PET/CT in NET patients, using both [18F]F-FDG/[68Ga]Ga-DOTA-somatostatin analog (SSA) for diagnosis and follow-up, is under discussion and could also result in a powerful prognostic tool. In addition, alternative strategies based on different metabolic pathways, radioisotopes, or combinations of different medical approaches could be applied. A number of different promising "doors" could thus open in the near future for the treatment of NET patients - and the "key" will be thera(g)nostic!
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Affiliation(s)
- Giulia Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria; Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Gianpaolo Di Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Irene Virgolini
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.
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Lawal IO, Abubakar SO, Ndlovu H, Mokoala KMG, More SS, Sathekge MM. Advances in Radioligand Theranostics in Oncology. Mol Diagn Ther 2024; 28:265-289. [PMID: 38555542 DOI: 10.1007/s40291-024-00702-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2024] [Indexed: 04/02/2024]
Abstract
Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.
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Affiliation(s)
- Ismaheel O Lawal
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, NE, Atlanta, GA, 30322, USA.
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa.
| | - Sofiullah O Abubakar
- Department of Radiology and Nuclear Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Honest Ndlovu
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
| | - Kgomotso M G Mokoala
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
| | - Stuart S More
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Division of Nuclear Medicine, Department of Radiation Medicine, University of Cape Town, Cape Town, 7700, South Africa
| | - Mike M Sathekge
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
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Perrone E, Ghai K, Eismant A, Andreassen M, Langer SW, Knigge U, Kjaer A, Baum RP. Impressive Response to TANDEM Peptide Receptor Radionuclide Therapy with 177Lu/ 225AcDOTA-LM3 Somatostatin Receptor Antagonist in a Patient with Therapy-Refractory, Rapidly Progressive Neuroendocrine Neoplasm of the Pancreas. Diagnostics (Basel) 2024; 14:907. [PMID: 38732321 PMCID: PMC11083426 DOI: 10.3390/diagnostics14090907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
The present report describes the history of a 58-year-old woman with a rapidly progressing neuroendocrine pancreatic tumor (initially G2) presenting with extensive liver, bone, and lymph node metastases. Previous treatments included chemotherapy, hemithyroidectomy for right lobe metastasis, Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTATATE, Lanreotide, Everolimus, and liver embolization. Due to severe disease progression, after a liver biopsy revealing tumor grade G3, PRRT with the somatostatin receptor antagonist LM3 was initiated. [68Ga]GaDOTA-LM3 PET/CT showed intense tracer uptake in the liver, pancreatic tumor, lymph nodes, and bone metastases. Three TANDEM-PRRT cycles using [177Lu]LuDOTA-LM3 and [225Ac]AcDOTA-LM3, administered concurrently, resulted in significant improvement, notably in liver metastases, hepatomegaly reduction, the complete regression of bone and lymph node metastases, and primary tumor improvement. Partial remission was confirmed by positron emission tomography/computed tomography, chest-abdomen-pelvis contrast-enhanced computed tomography, and magnetic resonance of the abdomen, with marked clinical improvement in pain, energy levels, and quality of life, enabling full resumption of physical activity.
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Affiliation(s)
- Elisabetta Perrone
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, 65191 Wiesbaden, Germany; (K.G.); (A.E.); (R.P.B.)
- Institute of Nuclear Medicine, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Kriti Ghai
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, 65191 Wiesbaden, Germany; (K.G.); (A.E.); (R.P.B.)
| | - Aleksandr Eismant
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, 65191 Wiesbaden, Germany; (K.G.); (A.E.); (R.P.B.)
| | - Mikkel Andreassen
- Department of Endocrinology, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark; (M.A.); (U.K.)
- ENETS Center of Excellence, 2100 Copenhagen, Denmark; (S.W.L.); (A.K.)
| | - Seppo W. Langer
- ENETS Center of Excellence, 2100 Copenhagen, Denmark; (S.W.L.); (A.K.)
- Department of Oncology, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark
| | - Ulrich Knigge
- Department of Endocrinology, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark; (M.A.); (U.K.)
- ENETS Center of Excellence, 2100 Copenhagen, Denmark; (S.W.L.); (A.K.)
| | - Andreas Kjaer
- ENETS Center of Excellence, 2100 Copenhagen, Denmark; (S.W.L.); (A.K.)
- Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Richard P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, 65191 Wiesbaden, Germany; (K.G.); (A.E.); (R.P.B.)
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Zhang T, Lei H, Chen X, Dou Z, Yu B, Su W, Wang W, Jin X, Katsube T, Wang B, Zhang H, Li Q, Di C. Carrier systems of radiopharmaceuticals and the application in cancer therapy. Cell Death Discov 2024; 10:16. [PMID: 38195680 PMCID: PMC10776600 DOI: 10.1038/s41420-023-01778-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 01/11/2024] Open
Abstract
Radiopharmaceuticals play a vital role in cancer therapy. The carrier of radiopharmaceuticals can precisely locate and guide radionuclides to the target, where radionuclides kill surrounding tumor cells. Effective application of radiopharmaceuticals depends on the selection of an appropriate carrier. Herein, different types of carriers of radiopharmaceuticals and the characteristics are briefly described. Subsequently, we review radiolabeled monoclonal antibodies (mAbs) and their derivatives, and novel strategies of radiolabeled mAbs and their derivatives in the treatment of lymphoma and colorectal cancer. Furthermore, this review outlines radiolabeled peptides, and novel strategies of radiolabeled peptides in the treatment of neuroendocrine neoplasms, prostate cancer, and gliomas. The emphasis is given to heterodimers, bicyclic peptides, and peptide-modified nanoparticles. Last, the latest developments and applications of radiolabeled nucleic acids and small molecules in cancer therapy are discussed. Thus, this review will contribute to a better understanding of the carrier of radiopharmaceuticals and the application in cancer therapy.
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Affiliation(s)
- Taotao Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Huiwen Lei
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Xiaohua Chen
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China
| | - Zhihui Dou
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Boyi Yu
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Wei Su
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Wei Wang
- College of Life Science, Northwest Normal University, Lanzhou, 730000, China
| | - Xiaodong Jin
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China
| | - Takanori Katsube
- National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan
| | - Bing Wang
- National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan
| | - Hong Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
| | - Qiang Li
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
| | - Cuixia Di
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
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Khazaei Monfared Y, Heidari P, Klempner SJ, Mahmood U, Parikh AR, Hong TS, Strickland MR, Esfahani SA. DNA Damage by Radiopharmaceuticals and Mechanisms of Cellular Repair. Pharmaceutics 2023; 15:2761. [PMID: 38140100 PMCID: PMC10748326 DOI: 10.3390/pharmaceutics15122761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/05/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
DNA is an organic molecule that is highly vulnerable to chemical alterations and breaks caused by both internal and external factors. Cells possess complex and advanced mechanisms, including DNA repair, damage tolerance, cell cycle checkpoints, and cell death pathways, which together minimize the potentially harmful effects of DNA damage. However, in cancer cells, the normal DNA damage tolerance and response processes are disrupted or deregulated. This results in increased mutagenesis and genomic instability within the cancer cells, a known driver of cancer progression and therapeutic resistance. On the other hand, the inherent instability of the genome in rapidly dividing cancer cells can be exploited as a tool to kill by imposing DNA damage with radiopharmaceuticals. As the field of targeted radiopharmaceutical therapy (RPT) is rapidly growing in oncology, it is crucial to have a deep understanding of the impact of systemic radiation delivery by radiopharmaceuticals on the DNA of tumors and healthy tissues. The distribution and activation of DNA damage and repair pathways caused by RPT can be different based on the characteristics of the radioisotope and molecular target. Here we provide a comprehensive discussion of the biological effects of RPTs, with the main focus on the role of varying radioisotopes in inducing direct and indirect DNA damage and activating DNA repair pathways.
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Affiliation(s)
- Yousef Khazaei Monfared
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (Y.K.M.); (P.H.); (U.M.)
| | - Pedram Heidari
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (Y.K.M.); (P.H.); (U.M.)
| | - Samuel J. Klempner
- Division of Hematology-Oncology, Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (S.J.K.); (A.R.P.); (M.R.S.)
| | - Umar Mahmood
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (Y.K.M.); (P.H.); (U.M.)
| | - Aparna R. Parikh
- Division of Hematology-Oncology, Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (S.J.K.); (A.R.P.); (M.R.S.)
| | - Theodore S. Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Matthew R. Strickland
- Division of Hematology-Oncology, Department of Medicine, Mass General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (S.J.K.); (A.R.P.); (M.R.S.)
| | - Shadi A. Esfahani
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; (Y.K.M.); (P.H.); (U.M.)
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11
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Wild D, Grønbæk H, Navalkissoor S, Haug A, Nicolas GP, Pais B, Ansquer C, Beauregard JM, McEwan A, Lassmann M, Pennestri D, Volteau M, Lenzo NP, Hicks RJ. A phase I/II study of the safety and efficacy of [ 177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2023; 51:183-195. [PMID: 37721581 PMCID: PMC10684626 DOI: 10.1007/s00259-023-06383-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/02/2023] [Indexed: 09/19/2023]
Abstract
PURPOSE We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 μg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment‑related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.
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Affiliation(s)
- Damian Wild
- Division of Nuclear Medicine, ENETS Centre of Excellence, University Hospital Basel, Basel, Switzerland.
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, ENETS Centre of Excellence, Aarhus University Hospital and Clinical Institute, Aarhus University, Aarhus, Denmark
| | - Shaunak Navalkissoor
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK
| | - Alexander Haug
- Department of Radiology and Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Guillaume P Nicolas
- Division of Nuclear Medicine, ENETS Centre of Excellence, University Hospital Basel, Basel, Switzerland
| | - Ben Pais
- SRT-Biomedical B.V., Soest, Netherlands
- Ariceum Therapeutics GmbH, Berlin, Germany
| | | | | | | | - Michael Lassmann
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | | | | | - Nat P Lenzo
- GenesisCare, East Fremantle, Australia
- Department of Medicine, Curtin University, Perth, Australia
| | - Rodney J Hicks
- Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne, Australia
- Department of Medicine, Central Clinical School, The Alfred Hospital, Monash University, Melbourne, Australia
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12
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Wang P, Liu S, Li X, Liu X, Li S, Wu Z, Cheng X. The usefulness of [ 68 Ga]Ga-DOTA-JR11 PET/CT in patients with meningioma: comparison with MRI. Eur J Nucl Med Mol Imaging 2023; 51:218-225. [PMID: 37682301 DOI: 10.1007/s00259-023-06391-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023]
Abstract
PURPOSE Clinical studies of PET imaging using SSTR2 agonists have demonstrated high accuracy and correlation with SSTR2 expression in meningiomas. However, the usefulness of the SSTR2 antagonist with [68 Ga]Ga-DOTA-JR11 is uncertain. To evaluate the diagnostic performance of [68 Ga]Ga-DOTA-JR11 PET/CT and to clarify tumor characteristics in patients with suspected meningiomas. MATERIALS AND METHODS Patients with suspected de novo or recurrent meningioma in complex locations or atypical images were enrolled from August 2021 to October 2022 in prospective study. All patients underwent contrast-enhanced MRI (CE-MRI), [68 Ga]Ga-DOTA-JR11 PET/CT, and histopathological evaluation. Tumor uptake of [68 Ga]Ga-DOTA-JR11 was measured by SUVmax and tumor-endocranium ratio (TBR). Diagnostic performance was compared between PET and MRI. RESULTS Of 36 (50.0 ± 13.0 years of age, 20 women) patients, 32 were histopathologically confirmed meningiomas and four with other tumors. [68 Ga]Ga-DOTA-JR11 uptake was significantly higher in meningioma patients than in those with other tumors (SUVmax: 13.6 ± 7.7 vs. 5.2 ± 3.0, P < 0.001; TBR: 64.2 ± 27.7 vs. 25.0 ± 18.9, P = 0.001). [68 Ga]Ga-DOTA-JR11 PET/CT detected 31 meningiomas, while CE-MRI detected 17 meningiomas of 25 initial diagnosis and 11 recurrent tumors; [68 Ga]Ga-DOTA-JR11 PET had an incremental diagnostic value of 24% (6/25) over MRI in the group of initial diagnosis. There was no statistically significant difference in diagnostic efficacy between PET and MRI (P = 0.45) for all 36 patients. In skull base meningiomas, PET provided a more definitive diagnosis of pituitary involvement (in 12, not in12), compared to MRI (in eight, possible in six, possible not in six, not in four). PET revealed bone involvement in all 14 patients proven by pathology, while MRI identified only 11. CONCLUSIONS [68 Ga]Ga-DOTA-JR11 PET/CT provided high image quality and presented an ideal diagnostic performance in detecting meningioma and evaluating the involvement of the pituitary and bone. The study provides valuable evidence for the use of [68 Ga]Ga-DOTA-JR11 PET/CT as a complementary imaging modality to CE-MRI in the evaluation of meningiomas.
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Affiliation(s)
- Peipei Wang
- Department of Nuclear Medicine, Beijing , Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Shuai Liu
- Department of Radiation Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Xiaojie Li
- Department of Neurosurgery, Fengtai District, Beijing Tiantan Hospital, Capital Medical University, No. 119, the West Southern 4Th Ring Road, Beijing, 100073, China
| | - Xing Liu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Shaowu Li
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhen Wu
- Department of Neurosurgery, Fengtai District, Beijing Tiantan Hospital, Capital Medical University, No. 119, the West Southern 4Th Ring Road, Beijing, 100073, China.
| | - Xin Cheng
- Department of Nuclear Medicine, Beijing , Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
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13
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Vorster M, Hadebe BP, Sathekge MM. Theranostics in breast cancer. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2023; 3:1236565. [PMID: 39355052 PMCID: PMC11440857 DOI: 10.3389/fnume.2023.1236565] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 07/21/2023] [Indexed: 10/03/2024]
Abstract
Introduction Breast cancer is a complex disease and constitutes the leading cause of cancer in women globally. Conventional treatment modalities include surgery, chemotherapy, radiation therapy, and hormonal therapy; all of these have their limitations and often result in significant side effects or toxicity. Targeted radionuclide therapy based on a theranostic approach has been successfully applied in several malignancies, such as prostate cancer, thyroid cancer, and neuro-endocrine tumours. Several studies have also highlighted the potential of theranostic applications in breast cancer. Aim This review aims to provide an overview of the most promising current and future theranostic approaches in breast cancer. Discussion The discussion includes pre-clinical as well as clinical data on some of the most successful targets used to date. Examples of potential theranostic approaches include those targeting the Human epidermal growth factor receptor 2 (HER2) expression, angiogenesis, aspects of the tumour microenvironment, Gastrin-releasing peptide receptor (GRPR), Prostate-specific membrane antigen (PSMA) and Chemokine receptor 4 (CXCR-4) expression. Several challenges to widespread clinical implementation remain, which include regulatory approval, access to the various radiopharmaceuticals and imaging technology, cost-effectiveness, and the absence of robust clinical data. Conclusion Theranostic approaches have the potential to greatly improve diagnosis, treatment, and outcomes for patients with breast cancer. More research is needed to fully explore the potential of such approaches and to identify the best potential targets, considering feasibility, costs, efficacy, side effects and outcomes.
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Affiliation(s)
- M. Vorster
- Department of Nuclear Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - B. P. Hadebe
- Department of Nuclear Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - M. M. Sathekge
- Department of Nuclear Medicine, University of Pretoria, Pretoria, South Africa
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Funeh CN, Bridoux J, Ertveldt T, De Groof TWM, Chigoho DM, Asiabi P, Covens P, D'Huyvetter M, Devoogdt N. Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy. Pharmaceutics 2023; 15:pharmaceutics15051378. [PMID: 37242621 DOI: 10.3390/pharmaceutics15051378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
The precise delivery of cytotoxic radiation to cancer cells through the combination of a specific targeting vector with a radionuclide for targeted radionuclide therapy (TRT) has proven valuable for cancer care. TRT is increasingly being considered a relevant treatment method in fighting micro-metastases in the case of relapsed and disseminated disease. While antibodies were the first vectors applied in TRT, increasing research data has cited antibody fragments and peptides with superior properties and thus a growing interest in application. As further studies are completed and the need for novel radiopharmaceuticals nurtures, rigorous considerations in the design, laboratory analysis, pre-clinical evaluation, and clinical translation must be considered to ensure improved safety and effectiveness. Here, we assess the status and recent development of biological-based radiopharmaceuticals, with a focus on peptides and antibody fragments. Challenges in radiopharmaceutical design range from target selection, vector design, choice of radionuclides and associated radiochemistry. Dosimetry estimation, and the assessment of mechanisms to increase tumor uptake while reducing off-target exposure are discussed.
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Affiliation(s)
- Cyprine Neba Funeh
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Jessica Bridoux
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Thomas Ertveldt
- Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
| | - Timo W M De Groof
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Dora Mugoli Chigoho
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Parinaz Asiabi
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Peter Covens
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Matthias D'Huyvetter
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
| | - Nick Devoogdt
- Laboratory for In Vivo Cellular and Molecular Imaging, Department of Medical Imaging, Vrije Universiteit Brussel, Laarbeeklaan 103/K.001, 1090 Brussels, Belgium
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15
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Wheless M, Das S. Systemic Therapy for Pancreatic Neuroendocrine Tumors. Clin Colorectal Cancer 2023; 22:34-44. [PMID: 36114085 DOI: 10.1016/j.clcc.2022.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/21/2022] [Accepted: 08/02/2022] [Indexed: 11/03/2022]
Abstract
Patients with metastatic or advanced pancreatic neuroendocrine tumors (NETs) carry poorer prognoses relative to patients with other NETs due to bulkier and often, more proliferative baseline disease. Patients with these tumors also possess more approved treatment options relative to patients with other NETs, making therapeutic sequencing nuanced. As such, defining optimal therapeutic sequencing and developing more potent cytoreductive treatments for patients are significant areas of research need in the field. Herein this review, we discuss the current systemic therapy landscape, our approach to therapeutic sequencing in the clinic and ongoing studies seeking to define optimal sequencing of systemic therapies, and novel therapeutics in development, for patients with pancreatic NETs. We limit the scope of this latter topic to agents with preclinical or clinical rationale over the last 8 years to provide a contemporary view of the drug development landscape and focus primarily on new types of peptide receptor radionuclide therapy, anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors and anti-vascular endothelial growth receptor tyrosine kinase inhibitor plus immunotherapy combinations.
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Affiliation(s)
- Margaret Wheless
- Vanderbilt University Medical Center, Department of Medicine, Nashville, TN
| | - Satya Das
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology and Oncology, Nashville, TN.
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Ahenkorah S, Cawthorne C, Murce E, Deroose CM, Cardinaels T, Seimbille Y, Bormans G, Ooms M, Cleeren F. Direct comparison of [18F]AlF-NOTA-JR11 and [18F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist. Nucl Med Biol 2023; 118-119:108338. [PMID: 37018875 DOI: 10.1016/j.nucmedbio.2023.108338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/14/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND [18F]AlF-NOTA-octreotide is an 18F-labeled somatostatin analogue which is a good clinical alternative for 68Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [18F]AlF-NOTA-JR11 and the agonist [18F]AlF-NOTA-octreotide as SSTR PET probes is available. Herein, we present the radiosynthesis of [18F]AlF-NOTA-JR11 and compare its NETs imaging properties directly with the established agonist radioligand [18F]AlF-NOTA-octreotide preclinically. METHODS [18F]AlF-NOTA-JR11 was synthesized in an automated synthesis module. The in vitro binding characteristics (IC50) of [natF]AlF-NOTA-JR11 and [natF]AlF-NOTA-octreotide were evaluated and the in vitro stability of [18F]AlF-NOTA-JR11 was determined in human serum. In vitro cell binding and internalization was performed with [18F]AlF-NOTA-JR11 and [18F]AlF-NOTA-octreotide using SSTR2 expressing cells and the pharmacokinetics were evaluated using μPET/CT in mice bearing BON1.SSTR2 tumor xenografts. RESULTS Excellent binding affinity for SSTR2 was found for [natF]AlF-NOTA-octreotide (IC50 of 25.7 ± 7.9 nM). However, the IC50 value for [natF]AlF-NOTA-JR11 (290.6 ± 71 nM) was 11-fold higher compared to [natF]AlF-NOTA-octreotide, indicating lower affinity for SSTR2. [18F]AlF-NOTA-JR11 was obtained in a good RCY (50 ± 6 %) but with moderate RCP of 94 ± 1 %. [18F]AlF-NOTA-JR11 demonstrated excellent stability in human serum (>95 % after 240 min). 2.7-fold higher cell binding was observed for [18F]AlF-NOTA-JR11 as compared to [18F]AlF-NOTA-octreotide after 60 min. μPET/CT images demonstrated comparable pharmacokinetics and tumor uptake between [18F]AlF-NOTA-JR11 (SUVmax: 3.7 ± 0.8) and [18F]AlF-NOTA-octreotide (SUVmax: 3.6 ± 0.4). CONCLUSIONS [18F]AlF-NOTA-JR11 was obtained in good RCY, albeit with a moderate RCP. The cell binding study showed significant higher binding of [18F]AlF-NOTA-JR11 compared to [18F]AlF-NOTA-octreotide, despite the higher IC50 value of AlF-NOTA-JR11. However, pharmacokinetics and in vivo tumor uptake was comparable for both radiotracers. Novel Al18F-labeled derivatives of JR11 with higher SSTR2 affinity should be developed for increased tumor uptake and NET imaging sensitivity.
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Dadgar H, Jafari E, Ahmadzadehfar H, Rekabpour SJ, Ravanbod MR, Kalantarhormozi M, Nabipour I, Assadi M. Feasibility and therapeutic potential of the 68Ga/177Lu-DOTATATE theranostic pair in patients with metastatic medullary thyroid carcinoma. ANNALES D'ENDOCRINOLOGIE 2023; 84:45-51. [PMID: 36126757 DOI: 10.1016/j.ando.2022.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/25/2022] [Accepted: 08/23/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND This study assessed: 1) the clinical efficacy of imaging with 68Ga-DOTATATE PET/CT (SSTR (somatostatin receptor)-PET) to detect medullary thyroid carcinoma (MTC); and 2) the therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in MTC patients. MATERIALS AND METHODS Patients with histologically proven MTC and suspected recurrence following thyroidectomy, based on raised serum calcitonin levels, underwent SSTR-PET. In addition, to evaluate the clinical efficacy and safety of PRRT, the patients with intense uptake on SSTR-PET or 99mTc-octreotide scintigraphy underwent PRRT. The Common Terminology Criteria for Adverse Events (version 4.03) was used to grade adverse events after PRRT. Treatment response was classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). RESULTS Twenty MTC patients (10 male, 10 female) with a median age of 48.5 years underwent SSTR-PET. SSTR-PET was positive in 17/20 patients (85%). Four of the 17 patients with positive SSTR-PET were scheduled for PRRT. In addition, 2 patients had positive 99mTc-octreotide scintigraphy results (Krenning score ≥ 2) and were scheduled for PRRT. Two of the 6 patients who underwent PRRT showed PR, 2 SD and 2 PD. Two patients died during the follow-up period. Median overall survival was 19 months (95% CI: 5.52-29.48). There were no cases of significant toxicity. CONCLUSION Radiolabeled somatostatin analogs are contributive for the management of recurrent MTC. 68Ga-DOTATAE PET-CT showed a relatively high detection rate in recurrent MTC. In addition, PRRT with 177Lu-DOTATATE was found to be a safe alternative therapeutic option for MTC.
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Affiliation(s)
- Habibollah Dadgar
- Cancer Research Center, Imam Reza International University, RAZAVI Hospital, Mashhad, Iran
| | - Esmail Jafari
- The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | | | | | - Mohammad Reza Ravanbod
- Department of Oncology, School of Medicine, Bushehr University of Medical Sciences, Bushehr Medical University Hospital, Bushehr, Iran
| | - Mohammadreza Kalantarhormozi
- Department of Internal Medicine (Division of Endocrinology), Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran; The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- Department of Internal Medicine (Division of Endocrinology), Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran; The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Majid Assadi
- The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Theranostics, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.
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Balma M, Liberini V, Buschiazzo A, Racca M, Rizzo A, Nicolotti DG, Laudicella R, Quartuccio N, Longo M, Perlo G, Terreno E, Abgral R, William Huellner M, Papaleo A, Deandreis D. The Role of Theragnostics in Breast Cancer: A Systematic Review of the Last 12 Years. Curr Med Imaging 2023; 19:817-831. [PMID: 36797602 DOI: 10.2174/1573405619666230216114748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 12/11/2022] [Accepted: 12/21/2022] [Indexed: 02/18/2023]
Abstract
BACKGROUND Breast cancer is the most common malignancy in women, with high morbidity and mortality. Molecular alterations in breast cancer involve the expression or upregulation of various molecular targets that can be used for diagnostic nuclear medicine imaging and radiopharmaceutical treatment. Theragnostics is based on the binding of radionuclides to molecular targets. These radionuclides can induce a cytotoxic effect on the specific tumor cell (target) or its vicinity, thus allowing a personalized approach to patients with effective treatment and comparably small side effects. AIM This review aims to describe the most promising molecular targets currently under investigation for theragnostics and precision oncology in breast cancer. METHODS A comprehensive literature search of studies on theragnostics in breast cancer was performed in the PubMed, PMC, Scopus, Google Scholar, Embase, Web of Science, and Cochrane library databases, between 2010 and 2022, using the following terms: breast neoplasm*, breast, breast cancer*, theragnostic*, theranostic*, radioligand therap*, RLT, MET, FLT, FMISO, FES, estradiol, trastuzumab, PD-L1, PSMA, FAPI, FACBC, fluciclovine, FAZA, GRPR, DOTATOC, DOTATATE, CXC4, endoglin, gastrin, mucin1, and syndecan1. RESULTS Fifty-three studies were included in the systematic review and summarized in six clinical sections: 1) human epidermal growth factor receptor 2 (HER2); 2) somatostatin receptors (SSTRS); 3) prostate-specific membrane antigen radiotracers (PSMA); 4) fibroblast activation protein-α targeted radiotracers; 5) gastrin-releasing peptide receptor-targeted radiotracers; 6) other radiotracers for theragnostics. CONCLUSION The theragnostic approach will progressively allow better patient selection, and improve the prediction of response and toxicity, avoiding unnecessary and costly treatment.
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Affiliation(s)
- Michele Balma
- Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
| | - Virginia Liberini
- Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
- Department of Medical Science, Division of Nuclear Medicine, University of Turin, Turin, Italy
| | - Ambra Buschiazzo
- Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
| | - Manuela Racca
- Nuclear Medicine Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Alessio Rizzo
- Nuclear Medicine Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | | | - Riccardo Laudicella
- Department of Biomedical and Dental Sciences and of Morpho-Functional Imaging, Nuclear Medicine Unit, University of Messina, Messina, Italy
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Nuclear Medicine Unit, Fondazione Istituto G. Giglio, Cefalù (Palermo), Italy
| | - Natale Quartuccio
- Nuclear Medicine Unit, A.R.N.A.S. Civico Di Cristina and Benfratelli Hospitals, Palermo, Italy
| | - Michelangelo Longo
- Cyclotron Unit, Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
| | - Giorgia Perlo
- Cyclotron Unit, Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
| | - Enzo Terreno
- Department of Molecular Biotechnology and Health Sciences, Molecular & Preclinical Imaging Centers, University of Turin, Turin, Italy
| | - Ronan Abgral
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
| | - Martin William Huellner
- Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Alberto Papaleo
- Nuclear Medicine Department, S. Croce e Carle Hospital, Cuneo, Italy
| | - Désirée Deandreis
- Department of Medical Science, Division of Nuclear Medicine, University of Turin, Turin, Italy
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Shi M, Jakobsson V, Greifenstein L, Khong PL, Chen X, Baum RP, Zhang J. Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. Front Med (Lausanne) 2022; 9:1034315. [PMID: 36569154 PMCID: PMC9767967 DOI: 10.3389/fmed.2022.1034315] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β- emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.
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Affiliation(s)
- Mengqi Shi
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Vivianne Jakobsson
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Academy for Precision Oncology, International Centers for Precision Oncology (ICPO), Wiesbaden, Germany
| | - Lukas Greifenstein
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
| | - Pek-Lan Khong
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Xiaoyuan Chen
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore
- Agency for Science, Technology, and Research (A*STAR), Institute of Molecular and Cell Biology, Singapore, Singapore
| | - Richard P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
| | - Jingjing Zhang
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Holzleitner N, Günther T, Beck R, Lapa C, Wester HJ. Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo. Pharmaceuticals (Basel) 2022; 15:ph15121467. [PMID: 36558917 PMCID: PMC9783573 DOI: 10.3390/ph15121467] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/23/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
In order to enable 18F- and 177Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as γ-linked D-glutamate chain were synthesised and evaluated. CCK-2R affinity (IC50, AR42J cells) and lipophilicity (logD7.4) were determined. Biodistribution studies at 24 h post-injection (p.i.) and µSPECT/CT imaging at 1, 4 and 24 h p.i. were carried out in AR42J tumour-bearing CB17-SCID mice. CCK-2R affinity of (R)-DOTAGA-rhCCK-1 to 18 was enhanced with increasing distance between the SiFA building block and the binding motif. Lipophilicity of [177Lu]Lu-(R)-DOTAGA-rhCCK-1 to 18 was higher compared to that of [177Lu]Lu-DOTA-PP-F11N and [177Lu]Lu-CP04. The respective α- and γ-linked rhCCK derivatives revealing the highest CCK-2R affinity were further evaluated in vivo. In comparison with [177Lu]Lu-DOTA-PP-F11N, [177Lu-]Lu-(R)-DOTAGA-rhCCK-9 and -16 exhibited three- to eight-fold increased activity levels in the tumour at 24 h p.i. However, activity levels in the kidneys were elevated as well. We could show that the introduction of a lipophilic SiFA moiety into the hydrophilic backbone of [177Lu]Lu-DOTA-PP-F11N led to a decelerated blood clearance and thus improved tumour retention. However, elevated kidney retention has to be addressed in future studies.
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Affiliation(s)
- Nadine Holzleitner
- Pharmaceutical Radiochemistry, Technical University of Munich, 85748 Garching, Germany
- Correspondence: (N.H.); (T.G.)
| | - Thomas Günther
- Pharmaceutical Radiochemistry, Technical University of Munich, 85748 Garching, Germany
- Correspondence: (N.H.); (T.G.)
| | - Roswitha Beck
- Pharmaceutical Radiochemistry, Technical University of Munich, 85748 Garching, Germany
| | - Constantin Lapa
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, 86156 Augsburg, Germany
| | - Hans-Jürgen Wester
- Pharmaceutical Radiochemistry, Technical University of Munich, 85748 Garching, Germany
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Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [ 153Sm]Sm-DOTA-TATE. Pharmaceutics 2022; 14:pharmaceutics14122566. [PMID: 36559060 PMCID: PMC9785812 DOI: 10.3390/pharmaceutics14122566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/12/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.
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22
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Ma X, Ding Y, Li W, Li Q, Yang H. Diagnosis and management of gastroenteropancreatic neuroendocrine neoplasms by nuclear medicine: Update and future perspective. Front Oncol 2022; 12:1061065. [PMID: 36483036 PMCID: PMC9722972 DOI: 10.3389/fonc.2022.1061065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/07/2022] [Indexed: 11/14/2023] Open
Abstract
Gastrointestinal (GI) cancers are the second most common cause of cancer related deaths in the World. Neuroendocrine neoplasms (NENs) is a rare tumor that originated from peptidergic neurons and neuroendocrine cells. NENs occurs in all parts of the body, especially in stomach, intestine, pancreas and lung. These rare tumors are challenging to diagnose at earlier stages because of their wide anatomical distribution and complex clinical features. Traditional imaging methods including magnetic resonance imaging (MRI) and computed tomography (CT) are mostly of useful for detection of larger primary tumors that are 1cm in size. A new medical imaging specialty called nuclear medicine uses radioactive substances for both diagnostic and therapeutic purposes. Nuclear medicine imaging relies on the tissue-specific uptake of radiolabeled tracers. Nuclear medicine techniques can easily identify the NENs tissues for their ability to absorb and concentrate amine, precursors, and peptides, whereas the traditional imaging methods are difficult to perform well. The somatostatin receptor (SSTR) is a targetable receptor frequently expressed in the gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), and is a promising target for tumor-targeted therapies and radiography. SSTR based somatostatin receptor imaging and peptide receptor radionuclide therapy (PRRT) has emerged as a new hot subject in the diagnosis and treatment of GEP-NENs due to the rapid development of somatostatin analogues (SSAs) and radionuclide. This review aims to provide an overview of the current status of nuclear medicine imaging modalities in the imaging of GEP-NENs, and puts them in perspective of clinical practice.
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Affiliation(s)
| | | | | | | | - Hui Yang
- Department of Nuclear Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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23
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Sun J, Huangfu Z, Yang J, Wang G, Hu K, Gao M, Zhong Z. Imaging-guided targeted radionuclide tumor therapy: From concept to clinical translation. Adv Drug Deliv Rev 2022; 190:114538. [PMID: 36162696 DOI: 10.1016/j.addr.2022.114538] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 09/03/2022] [Accepted: 09/11/2022] [Indexed: 01/24/2023]
Abstract
Since the first introduction of sodium iodide I-131 for use with thyroid patients almost 80 years ago, more than 50 radiopharmaceuticals have reached the markets for a wide range of diseases, especially cancers. The nuclear medicine paradigm also shifts from solely molecular imaging or radionuclide therapy to imaging-guided radionuclide therapy, which is deemed a vital component of precision cancer therapy and an emerging medical modality for personalized medicine. The imaging-guided radionuclide therapy highlights the systematic integration of targeted nuclear diagnostics and radionuclide therapeutics. Regarding this, nuclear imaging serves to "visualize" the lesions and guide the therapeutic strategy, followed by administration of a precise patient specific dose of radiotherapeutics for treatment according to the absorbed dose to different organs and tumors calculated by dosimetry tools, and finally repeated imaging to predict the prognosis. This strategy leads to significantly enhanced therapeutic efficacy, improved patient outcomes, and manageable adverse events. In this review, we provide an overview of imaging-guided targeted radionuclide therapy for different tumors such as advanced prostate cancer and neuroendocrine tumors, with a focus on development of new radioligands and their preclinical and clinical results, and further discuss about challenges and future perspectives.
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Affiliation(s)
- Juan Sun
- College of Pharmaceutical Sciences, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China; Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Zhenyuan Huangfu
- College of Pharmaceutical Sciences, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China; Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Jiangtao Yang
- College of Pharmaceutical Sciences, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China; Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Guanglin Wang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China.
| | - Kuan Hu
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
| | - Mingyuan Gao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, People's Republic of China
| | - Zhiyuan Zhong
- College of Pharmaceutical Sciences, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, People's Republic of China; Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.
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Koustoulidou S, Handula M, de Ridder C, Stuurman D, Beekman S, de Jong M, Nonnekens J, Seimbille Y. Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors. Pharmaceuticals (Basel) 2022; 15:ph15091155. [PMID: 36145375 PMCID: PMC9503898 DOI: 10.3390/ph15091155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/07/2022] [Accepted: 09/13/2022] [Indexed: 11/18/2022] Open
Abstract
Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment. Therefore, two JR11 analogs (8a and 8b), each carrying an albumin binding domain, were designed to prolong the blood residence time of JR11. Both compounds were labeled with lutetium-177 and evaluated via in vitro assays, followed by in vivo SPECT/CT imaging and ex vivo biodistribution studies. [177Lu]Lu-8a and [177Lu]Lu-8b were obtained with high radiochemical purity (>97%) and demonstrated excellent stability in PBS and mouse serum (>95%). [177Lu]Lu-8a showed better affinity towards human albumin compared to [177Lu]Lu-8b. Further, 8a and 8b exhibited binding affinities 30- and 48-fold lower, respectively, than that of the parent peptide JR11, along with high cell uptake and low internalization rate. SPECT/CT imaging verified high tumor accumulation for [177Lu]Lu-8a and [177Lu]Lu-JR11 at 4, 24, 48, and 72 h post-injection, but no tumor uptake was observed for [177Lu]Lu-8b. Ex vivo biodistribution studies revealed high and increasing tumor uptake for [177Lu]Lu-8a. However, its extended blood circulation led to an unfavorable biodistribution profile for radionuclide therapy.
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Affiliation(s)
- Sofia Koustoulidou
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Maryana Handula
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Corrina de Ridder
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Debra Stuurman
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Savanne Beekman
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Marion de Jong
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Julie Nonnekens
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Yann Seimbille
- Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
- Life Sciences Division, TRIUMF, Vancouver, BC V6T 2A3, Canada
- Correspondence: ; Tel.: +31-10-703-8961
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Comparison of the Anti-Tumour Activity of the Somatostatin Receptor (SST) Antagonist [177Lu]Lu-Satoreotide Tetraxetan and the Agonist [177Lu]Lu-DOTA-TATE in Mice Bearing AR42J SST2-Positive Tumours. Pharmaceuticals (Basel) 2022; 15:ph15091085. [PMID: 36145306 PMCID: PMC9506113 DOI: 10.3390/ph15091085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Limited experiments have compared the treatment effects of repetitive cycles of radiolabelled somatostatin (SST) analogues. In vitro and in vivo experiments were conducted in an AR42J cancer cell model, comparing the antagonist [177Lu]Lu-satoreotide tetraxetan with the agonist [177Lu]Lu-DOTA-TATE in terms of their binding properties, biodistribution, anti-tumour activity and toxicity. Histopathological and immunohistochemical examinations were performed at different timepoints. In the in vitro assays, [177Lu]Lu-satoreotide tetraxetan recognised twice as many SST2 binding sites as [177Lu]Lu-DOTA-TATE. In mice treated once a week for four consecutive weeks, [177Lu]Lu-satoreotide tetraxetan (15 MBq) revealed a significantly greater median time taken to reach a tumour volume of 850 mm3 (68 days) compared to [177Lu]Lu-DOTA-TATE at 15 MBq (43 days) or 30 MBq (48 days). This was associated with a higher tumour uptake, enhanced DNA damage and no or mild effects on body weight, haematological toxicity, or renal toxicity with [177Lu]Lu-satoreotide tetraxetan (15 MBq). At the end of the study, complete tumour senescence was noted in 20% of animals treated with [177Lu]Lu-satoreotide tetraxetan, in 13% of those treated with [177Lu]Lu-DOTA-TATE at 30 MBq, and in none of those treated with [177Lu]Lu-DOTA-TATE at 15 MBq. In conclusion, repeated administrations of [177Lu]Lu-satoreotide tetraxetan were able to potentiate peptide receptor radionuclide therapy with a higher tumour uptake, longer median survival, and enhanced DNA damage, with a favourable efficacy/safety profile compared to [177Lu]Lu-DOTA-TATE.
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Grey N, Silosky M, Lieu CH, Chin BB. Current status and future of targeted peptide receptor radionuclide positron emission tomography imaging and therapy of gastroenteropancreatic-neuroendocrine tumors. World J Gastroenterol 2022; 28:1768-1780. [PMID: 35633909 PMCID: PMC9099199 DOI: 10.3748/wjg.v28.i17.1768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/07/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Theranostics is the highly targeted molecular imaging and therapy of tumors. Targeted peptide receptor radionuclide therapy has taken the lead in demonstrating the safety and effectiveness of this molecular approach to treating cancers. Metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors may be most effectively imaged and treated with DOTATATE ligands. We review the current practice, safety, advantages, and limitations of DOTATATE based theranostics. Finally, we briefly describe the exciting new areas of development and future directions of gastroenteropancreatic neuroendocrine tumor theranostics.
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Affiliation(s)
- Neil Grey
- Radiology-Nuclear Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Michael Silosky
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Christopher H Lieu
- Medical Oncology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Bennett B Chin
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
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Vahidfar N, Farzanehfar S, Abbasi M, Mirzaei S, Delpassand ES, Abbaspour F, Salehi Y, Biersack HJ, Ahmadzadehfar H. Diagnostic Value of Radiolabelled Somatostatin Analogues for Neuroendocrine Tumour Diagnosis: The Benefits and Drawbacks of [ 64Cu]Cu-DOTA-TOC. Cancers (Basel) 2022; 14:1914. [PMID: 35454822 PMCID: PMC9027354 DOI: 10.3390/cancers14081914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 02/04/2023] Open
Abstract
Neuroendocrine tumours (NETs) arise from secondary epithelial cell lines in the gastrointestinal or respiratory system organs. The rate of development of these tumours varies from an indolent to an aggressive course, typically being initially asymptomatic. The identification of these tumours is difficult, particularly because the primary tumour is often small and undetectable by conventional anatomical imaging. Consequently, diagnosis of NETs is complicated and has been a significant challenge until recently. In the last 30 years, the advent of novel nuclear medicine diagnostic procedures has led to a substantial increase in NET detection. Great varieties of exclusive single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals for detecting NETs are being applied successfully in clinical settings, including [111In]In-pentetreotide, [99mTc]Tc-HYNIC-TOC/TATE, [68Ga]Ga-DOTA-TATE, and [64Cu]Cu-DOTA-TOC/TATE. Among these tracers for functional imaging, PET radiopharmaceuticals are clearly and substantially superior to planar or SPECT imaging radiopharmaceuticals. The main advantages include higher resolution, better sensitivity and increased lesion-to-background uptake. An advantage of diagnosis with a radiopharmaceutical is the capacity of theranostics to provide concomitant diagnosis and treatment with particulate radionuclides, such as beta and alpha emitters including Lutetium-177 (177Lu) and Actinium-225 (225Ac). Due to these unique challenges involved with diagnosing NETs, various PET tracers have been developed. This review compares the clinical characteristics of radiolabelled somatostatin analogues for NET diagnosis, focusing on the most recently FDA-approved [64Cu]Cu-DOTA-TATE as a state-of-the art NET-PET/CT radiopharmaceutical.
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Affiliation(s)
- Nasim Vahidfar
- Department of Nuclear Medicine, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran 1419733133, Iran; (N.V.); (S.F.); (M.A.); (Y.S.)
| | - Saeed Farzanehfar
- Department of Nuclear Medicine, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran 1419733133, Iran; (N.V.); (S.F.); (M.A.); (Y.S.)
| | - Mehrshad Abbasi
- Department of Nuclear Medicine, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran 1419733133, Iran; (N.V.); (S.F.); (M.A.); (Y.S.)
| | - Siroos Mirzaei
- Clinic Ottakring, Institute of Nuclear Medicine with PET-Center, 1220 Vienna, Austria;
| | - Ebrahim S. Delpassand
- RadioMedix, Inc., Houston, TX 77041, USA;
- Excel Diagnostics and Nuclear Oncology Center, Houston, TX 77042, USA
| | - Farzad Abbaspour
- Division of Nuclear Medicine, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON K1H 8L6, Canada;
| | - Yalda Salehi
- Department of Nuclear Medicine, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran 1419733133, Iran; (N.V.); (S.F.); (M.A.); (Y.S.)
| | - Hans Jürgen Biersack
- Department of Nuclear Medicine, University Hospital Bonn, 53127 Bonn, Germany;
- Betaklinik Bonn, 53227 Bonn, Germany
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Fani M, Mansi R, Nicolas GP, Wild D. Radiolabeled Somatostatin Analogs-A Continuously Evolving Class of Radiopharmaceuticals. Cancers (Basel) 2022; 14:cancers14051172. [PMID: 35267479 PMCID: PMC8909681 DOI: 10.3390/cancers14051172] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 11/16/2022] Open
Abstract
Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST2) being the predominantly and most frequently expressed. PET/CT imaging with 68Ga-labeled SST agonists, e.g., 68Ga-DOTA-TOC (SomaKit TOC®) or 68Ga-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 177Lu-DOTA-TOC or 177Lu-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 SST2 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 225Ac, or β- and Auger electrons, such as 161Tb, 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.
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Affiliation(s)
- Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, University Hospital Basel, 4031 Basel, Switzerland;
- Correspondence:
| | - Rosalba Mansi
- Division of Radiopharmaceutical Chemistry, University Hospital Basel, 4031 Basel, Switzerland;
| | - Guillaume P. Nicolas
- Division of Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland; (G.P.N.); (D.W.)
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, 4031 Basel, Switzerland
| | - Damian Wild
- Division of Nuclear Medicine, University Hospital Basel, 4031 Basel, Switzerland; (G.P.N.); (D.W.)
- ENETS Center of Excellence for Neuroendocrine and Endocrine Tumors, University Hospital Basel, 4031 Basel, Switzerland
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Peptide Receptor Radionuclide Therapy with [ 177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions. Cancers (Basel) 2022; 14:cancers14030584. [PMID: 35158852 PMCID: PMC8833790 DOI: 10.3390/cancers14030584] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Neuroendocrine neoplasms have been usually described as infrequent tumors, but their incidence has been rising over time. [177Lu]Lu-DOTA-TATE (PRRT-Lu) was approved by the European Medicines Agency and by the Food and Drug Administration as the first radiopharmaceutical for peptide receptor radionuclide therapy in progressive gastroenteropancreatic NET. PRRT-Lu is considered a therapeutic option in progressive SSTR-positive NETs with homogenous SSTR expression. The NETTER-1 study demonstrated that PRRT-Lu yielded a statistically and clinically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001), as well as a clinical trend towards improvement in OS. These results made scientific societies incorporate PRRT-Lu into their clinical guidelines; however, some questions still remain unanswered. Abstract This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.
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Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE. Rev Esp Med Nucl Imagen Mol 2022. [DOI: 10.1016/j.remn.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies. Cancers (Basel) 2021; 14:cancers14010129. [PMID: 35008293 PMCID: PMC8749814 DOI: 10.3390/cancers14010129] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/13/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Peptide receptor radionuclide therapy (PRRT) is a systemic treatment consisting of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. This will subsequently cause lethal DNA damage to the tumor cell. The only target that is currently used in widespread clinical practice is the somatostatin receptor, which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review focuses on the basic principles and clinical applications of PRRT, and discusses several PRRT-optimization strategies. Abstract Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose–effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.
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Prado-Wohlwend S, Bernal-Vergara JC, Utrera-Costero A, Cañón-Sánchez JR, Agudelo-Cifuentes M, Bello-Arques P. Peptide receptor radionuclide therapy with [ 177Lu]Lu-DOTA-TATE. Rev Esp Med Nucl Imagen Mol 2021; 41:55-65. [PMID: 34920969 DOI: 10.1016/j.remnie.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/10/2021] [Indexed: 11/30/2022]
Abstract
This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin receptors, the selection of patients for radiolabelled peptide therapy (PRRT), the inclusion criteria to benefit from treatment with the minimum possible adverse effects, the administration protocol, follow-up and response evaluation. The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out, and constitute the cornerstone for the development of teragnosis. Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options, and among the future perspectives, there are several lines of research to improve the objective response rate and survival with PRRT, focused on the development of new agonists and somatostatin receptor antagonists, new radionuclides and radiosensitizing combination therapies. In conclusion, PRRT is a great therapeutic, well-tolerated and safe tool with generally mild and self-limited acute side effects, that must be sequenced at the best moment of the evolution of the disease of patients with NET. Candidate patients for PRRT should always be evaluated by a multidisciplinary clinical committee.
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Affiliation(s)
- S Prado-Wohlwend
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
| | - J C Bernal-Vergara
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - A Utrera-Costero
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - J R Cañón-Sánchez
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - M Agudelo-Cifuentes
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - P Bello-Arques
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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Zhu W, Jia R, Yang Q, Cheng Y, Zhao H, Bai C, Xu J, Yao S, Huo L. A prospective randomized, double-blind study to evaluate the diagnostic efficacy of 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3 in patients with well-differentiated neuroendocrine tumors: compared with 68Ga-DOTATATE. Eur J Nucl Med Mol Imaging 2021; 49:1613-1622. [PMID: 34874478 DOI: 10.1007/s00259-021-05512-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/27/2021] [Indexed: 01/18/2023]
Abstract
PURPOSE The purpose of this study is to evaluate the diagnostic efficacy of 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 and compare them with 68 Ga-DOTATATE in patients with well-differentiated neuroendocrine tumors. METHODS Patients were prospectively recruited and equally randomized into two arms: Arm A, patients would undergo a whole-body 68 Ga-NODAGA-LM3 PET/CT scan on the 1st day and 68 Ga-DOTATATE PET/CT scan on the 2nd day; Arm B, patients would undergo a whole-body 68 Ga-DOTA-LM3 PET/CT scan on the 1st day and 68 Ga-DOTATATE PET/CT scan on the 2nd day. Biodistribution in normal organs, lesion detection ability, and tumor uptake were compared between antagonist and agonist in each arm. RESULTS A total of 40 patients with well-differentiated NETs, 20 in each arm, were recruited in the study. 68 Ga-NODAGA-LM3 showed a similar pattern as 68 Ga-DOTATATE, while 68 Ga-DOTA-LM3 demonstrated significantly lower uptake in almost all normal organs compared to 68 Ga-DOTATATE. Both 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 showed superiority in lesion detection compared to 68 Ga-DOTATATE on lesion-based and patient-based comparison. 68 Ga-NODAGA-LM3 showed a significantly higher tumor uptake (median SUVmax 29.1 versus 21.6, P < 0.05) and tumor-to-background ratio (median tumor-to-liver ratio 5.0 versus 2.9, P < 0.05) compared to 68 Ga-DOTATATE. 68 Ga-DOTA-LM3 showed comparable uptake (median SUVmax 16.1 versus 17.8, P = 0.714) and higher tumor-to-background ratio (median tumor-to-liver ratio 5.2 versus 2.1, P < 0.05). CONCLUSION Both 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 are promising SSTR2 antagonists for neuroendocrine tumors. They demonstrated superiority in diagnostic efficacy compared to agonist 68 Ga-DOTATATE. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT04318561.
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Affiliation(s)
- Wenjia Zhu
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Ru Jia
- Department of Gastrointestinal Oncology, the Fifth Medical Center, General Hospital of PLA, No. 8, East Avenue, Fengtai District, Beijing, China
| | - Qiao Yang
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China
| | - Yuejuan Cheng
- Department of Oncology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunmei Bai
- Department of Oncology, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, the Fifth Medical Center, General Hospital of PLA, No. 8, East Avenue, Fengtai District, Beijing, China
| | - Shaobo Yao
- Department Nuclear Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China
| | - Li Huo
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [ 177Lu]Lu-OPS201 Compared to the Agonist [ 177Lu]Lu-DOTA-TATE. Pharmaceuticals (Basel) 2021; 14:ph14121265. [PMID: 34959665 PMCID: PMC8706879 DOI: 10.3390/ph14121265] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 01/14/2023] Open
Abstract
Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST2) peptide agonist [177Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST2 peptide antagonist [177Lu]Lu-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 [177Lu]Lu-OPS201 versus [177Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST2. While [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE exhibited comparable affinity (KD, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively), [177Lu]Lu-OPS201 recognized four times more binding sites than [177Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [177Lu]Lu-OPS201 bound to HEK-SST2 cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [177Lu]Lu-OPS201 showed faster association and slower dissociation than [177Lu]Lu-DOTA-TATE. Whereas most of [177Lu]Lu-OPS201 remained at the cell surface, [177Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [177Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [177Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [177Lu]Lu-OPS201 compared to [177Lu]Lu-DOTA-TATE.
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Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms. Biomedicines 2021; 9:biomedicines9121810. [PMID: 34944626 PMCID: PMC8699000 DOI: 10.3390/biomedicines9121810] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/26/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.
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Meester EJ, Krenning BJ, de Blois E, de Jong M, van der Steen AFW, Bernsen MR, van der Heiden K. Imaging inflammation in atherosclerotic plaques, targeting SST 2 with [ 111In]In-DOTA-JR11. J Nucl Cardiol 2021; 28:2506-2513. [PMID: 32026330 PMCID: PMC8709817 DOI: 10.1007/s12350-020-02046-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/24/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Imaging Somatostatin Subtype Receptor 2 (SST2) expressing macrophages by [DOTA,Tyr3]-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST2 targeting ligand with a five times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection. METHODS AND RESULTS Atherosclerotic ApoE-/- mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of [111In]In-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of [111In]In-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed [111In]In-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST2 expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed [111In]In-DOTA-JR11 uptake at plaque locations containing CD68 and SST2 expressing cells. CONCLUSIONS The results of this study indicate DOTA-JR11 as a promising ligand for visualization of atherosclerotic plaque inflammation.
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Affiliation(s)
- Eric J Meester
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | | | - Erik de Blois
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Marion de Jong
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Antonius F W van der Steen
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Monique R Bernsen
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Kim van der Heiden
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
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Aerts A, Eberlein U, Holm S, Hustinx R, Konijnenberg M, Strigari L, van Leeuwen FWB, Glatting G, Lassmann M. EANM position paper on the role of radiobiology in nuclear medicine. Eur J Nucl Med Mol Imaging 2021; 48:3365-3377. [PMID: 33912987 PMCID: PMC8440244 DOI: 10.1007/s00259-021-05345-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 03/28/2021] [Indexed: 12/16/2022]
Abstract
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
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Affiliation(s)
- An Aerts
- Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Uta Eberlein
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
| | - Sören Holm
- Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark
| | - Roland Hustinx
- Division of Nuclear Medicine and Oncological Imaging, University Hospital of Liège, GIGA-CRC in vivo Imaging, University of Liège, Liège, Belgium
| | - Mark Konijnenberg
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Lidia Strigari
- Medical Physics Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fijs W B van Leeuwen
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerhard Glatting
- Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, Germany
| | - Michael Lassmann
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
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Zhu W, Cheng Y, Jia R, Zhao H, Bai C, Xu J, Yao S, Huo L. A Prospective, Randomized, Double-Blind Study to Evaluate the Safety, Biodistribution, and Dosimetry of 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3 in Patients with Well-Differentiated Neuroendocrine Tumors. J Nucl Med 2021; 62:1398-1405. [PMID: 33579804 PMCID: PMC8724897 DOI: 10.2967/jnumed.120.253096] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 01/27/2021] [Indexed: 12/19/2022] Open
Abstract
68Ga-NODAGA-LM3 (where LM3 is p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2) and 68Ga-DOTA-LM3 are somatostatin receptor subtype 2 (SSTR2)-specific antagonists used for PET/CT imaging. The purpose of this study was to evaluate the safety, biodistribution, and dosimetry of 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3 in patients with well-differentiated neuroendocrine tumors. Methods: Patients were equally randomized into 2 arms, with arm A receiving 68Ga-NODAGA-LM3 and arm B receiving 68Ga-DOTA-LM3. Serial PET scans were acquired at 5, 15, 30, 45, 60, and 120 min after 68Ga-NODAGA-LM3 (200 MBq ± 11 MBq/40 μg of total peptide mass) or 68Ga-DOTA-LM3 (172 MBq ± 21 MBq/40 μg of total peptide mass) injection. The biodistribution in normal organs, tumor uptake, and safety were assessed. Radiation dosimetry was calculated using OLINDA/EXM (version 1.0). Results: Sixteen patients, 8 in each arm, were recruited in the study. Both tracers were well tolerated in most patients. Two patients in arm B had nausea (grade 2), and one of them had vomiting (grade 1). The PET images of the other 14 patients were further analyzed. Significantly lower organ uptake was observed in the pituitary, parotids, liver, spleen, pancreas, adrenal, stomach, small intestine, and kidneys with 68Ga-DOTA-LM3 than with 68Ga-NODAGA-LM3. In total, 38 lesions were analyzed, including 18 with 68Ga-NODAGA-LM3 and 20 with 68Ga-DOTA-LM3. Both tracers showed good tumor uptake and retention. With 68Ga-NODAGA-LM3, the tracer accumulation in tumor lesions increased by 138%, from an average SUVmax of 31.3 ± 19.7 at 5 min to 74.6 ± 56.3 at 2 h. With 68Ga-DOTA-LM3, the tumor uptake rapidly reached a high level at 5 min after injection, with an average SUVmax of 36.6 ± 23.6, and continued to increase to 45.3 ± 29.3 until 30 min after injection. The urinary bladder wall was the organ receiving the highest absorbed dose in both arms. The mean effective dose was 0.026 ± 0.003 mSv/MBq for 68Ga-NODAGA-LM3 and 0.025 ± 0.002 mSv/MBq for 68Ga-DOTA-LM3. Conclusion: Both 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3 show favorable biodistribution, high tumor uptake, and good tumor retention, resulting in high image contrast. The dosimetric data are comparable to those for other 68Ga-labeled SSTR2 antagonists. Further studies are required to look into the potential antagonistic effects of 68Ga-NODAGA-LM3 and 68Ga-DOTA-LM3.
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Affiliation(s)
- Wenjia Zhu
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, CAMS and PUMC, Beijing, China
| | - Yuejuan Cheng
- Department of Oncology, Peking Union Medical College Hospital, Beijing, China
| | - Ru Jia
- Department of Gastrointestinal Oncology, Fifth Medical Center, General Hospital of PLA, Beijing, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; and
| | - Chunmei Bai
- Department of Oncology, Peking Union Medical College Hospital, Beijing, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, Fifth Medical Center, General Hospital of PLA, Beijing, China
| | - Shaobo Yao
- Department Nuclear Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Li Huo
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, CAMS and PUMC, Beijing, China;
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Comparing the Effect of Multiple Histone Deacetylase Inhibitors on SSTR2 Expression and [ 111In]In-DOTATATE Uptake in NET Cells. Cancers (Basel) 2021; 13:cancers13194905. [PMID: 34638389 PMCID: PMC8508045 DOI: 10.3390/cancers13194905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 01/23/2023] Open
Abstract
Simple Summary Patients diagnosed with neuroendocrine tumors (NETs) are often treated with peptide receptor radionuclide therapy (PRRT). This therapy targets the somatostatin type-2 receptors (SSTR2) frequently overexpressed on these types of tumors. Although this therapy has proven to be effective, complete responses are rare and therapy improvement is desirable. We aimed to increase SSTR2 expression on NET cells, potentially increasing the number of patients eligible for SSTR2-targeted PRRT and improving clinical outcomes. We used histone deacetylase inhibitors (HDACis) to manipulate the epigenetic machinery and hereby aimed to increase SSTR2 gene transcription. Our results showed that the HDACis increased SSTR2 expression in several NET cell lines. Moreover, the uptake of radiolabeled DOTATATE, the tracer used for PRRT, was enhanced. The observed reversibility profile after HDACi withdrawal of the induced effects suggests that proper timing of HDACi treatment is likely essential. Abstract The aim of this study was to increase somatostatin type-2 receptor (SSTR2) expression on neuroendocrine tumor (NET) cells using histone deacetylase inhibitors (HDACis), potentially increasing the uptake of SSTR2-targeted radiopharmaceuticals and subsequently improving treatment efficacy of peptide receptor radionuclide therapy (PRRT). Human NET cell lines BON-1, NCI-H727, and GOT1 were treated with HDACis (i.e., CI-994, entinostat, LMK-235, mocetinostat, panobinostat, or valproic acid (VPA); entinostat and VPA were the HDACis tested in GOT1 cells) to examine SSTR2 mRNA expression levels and uptake of SSTR2-targeting radiotracer [111In]In-DOTATATE. Reversibility of the induced effects was examined after drug-withdrawal. Finally, the effect of VPA on radiosensitivity was investigated. A strong stimulatory effect in BON-1, NCI-H727, and GOT1 cells was observed after HDACi treatment, both on SSTR2 mRNA expression levels and [111In]In-DOTATATE uptake. The effects of the HDACis were largely reversible over a period of seven days, demonstrating largest reductions within the first day. The reversibility profile of the induced effects suggests that proper timing of HDACi treatment is most likely essential for a beneficial outcome. In addition to increasing SSTR2 expression levels, VPA enhanced the radiosensitivity of all cell lines. In conclusion, HDACi treatment increased SSTR2 expression, and radiosensitivity was also enhanced upon VPA treatment.
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Jokar N, Velikyan I, Ahmadzadehfar H, Rekabpour SJ, Jafari E, Ting HH, Biersack HJ, Assadi M. Theranostic Approach in Breast Cancer: A Treasured Tailor for Future Oncology. Clin Nucl Med 2021; 46:e410-e420. [PMID: 34152118 DOI: 10.1097/rlu.0000000000003678] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT Breast cancer is the most frequent invasive malignancy and the second major cause of cancer death in female subjects mostly due to the considerable diagnostic delay and failure of therapeutic strategies. Thus, early diagnosis and possibility to monitor response to the treatment are of utmost importance. Identification of valid biomarkers, in particular new molecular therapeutic targets, that would allow screening, early patient identification, prediction of disease aggressiveness, and monitoring response to the therapeutic regimen has been in the focus of breast cancer research during recent decades. One of the intensively developing fields is nuclear medicine combining molecular diagnostic imaging and subsequent (radio)therapy in the light of theranostics. This review aimed to survey the current status of preclinical and clinical research using theranostic approach in breast cancer patients with potential to translate into conventional treatment strategies alone or in combination with other common treatments, especially in aggressive and resistant types of breast cancer. In addition, we present 5 patients with breast cancer who were refractory or relapsed after conventional therapy while presumably responded to the molecular radiotherapy with 177Lu-trastuzumab (Herceptin), 177Lu-DOTATATE, and 177Lu-FAPI-46.
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Affiliation(s)
- Narges Jokar
- From the The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Irina Velikyan
- Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | | | - Esmail Jafari
- From the The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hong Hoi Ting
- Nanomab Technology Limited, Shanghai, People's Republic of China
| | | | - Majid Assadi
- From the The Persian Gulf Nuclear Medicine Research Center, Department of Molecular Imaging and Radionuclide Therapy, Bushehr Medical University Hospital, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
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Das S, Dasari A. Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors. Ther Adv Med Oncol 2021; 13:17588359211018047. [PMID: 34093744 PMCID: PMC8141991 DOI: 10.1177/17588359211018047] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent the most common subtype of NETs. The incidence of all NETs, and specifically GEP NETs, has risen exponentially over the last three decades. Only within the past several years have these tumors been appropriately classified, allowing for meaningful drug development. Broadly, some of the most exciting drug classes being developed for patients with well-differentiated GEP NETs include newer types of peptide receptor radionuclide therapy (PRRT) or combinations which increase the potency of lutetium-177 (177Lu)-Dotatate, novel multi-target receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy modalities, beyond checkpoint inhibitors, which seek to unleash the immune system against NETs. Specifically looking at newer types of PRRT, somatostatin receptor antagonists and alpha-emitter radionuclides each have demonstrated the ability to elicit greater DNA damage than 177Lu-Dotatate in preclinical models. Early clinical experiences with each of these agents suggest they may be more cytotoxic than 177Lu-Dotatate. Other approaches seeking to build upon the DNA damage created by 177Lu-Dotatate include combinations of PRRT with radiosensitizers such as heat shock protein 90 inhibitors, hedgehog inhibitors, chemotherapy combinations, and triapine. Many of these combinations have just begun to be tested clinically. With regards to novel RTKIs, some of the ones which have demonstrated potent cytoreductive potential include cabozantinib and lenvatinib. Other RTKIs which are further along the clinical development spectrum and have demonstrated benefit in randomized trials include surufatinib and pazopanib. And though single-agent immune checkpoint inhibitors have not demonstrated significant anti-tumor activity in patients with GEP NETs, outside of certain biomarker selected subsets, somatostatin receptor-directed chimeric antigen receptor (CAR) T cells and vaccines such as SurVaxM, which targets survivin, represent two means through which NET-directed immunity may be modulated. The potential of these agents, if clinically realized, will likely improve outcomes for patients with well-differentiated GEP NETs.
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Affiliation(s)
- Satya Das
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Arvind Dasari
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
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Damiana TST, Dalm SU. Combination Therapy, a Promising Approach to Enhance the Efficacy of Radionuclide and Targeted Radionuclide Therapy of Prostate and Breast Cancer. Pharmaceutics 2021; 13:pharmaceutics13050674. [PMID: 34067215 PMCID: PMC8151894 DOI: 10.3390/pharmaceutics13050674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/21/2022] Open
Abstract
In recent years, radionuclide therapy (RT) and targeted radionuclide therapy (TRT) have gained great interest in cancer treatment. This is due to promising results obtained in both preclinical and clinical studies. However, a complete response is achieved in only a small percentage of patients that receive RT or TRT. As a consequence, there have been several strategies to improve RT and TRT outcomes including the combination of these treatments with other well-established anti-cancer therapies, for example, chemotherapy. Combinations of RT and TRT with other therapies with distinct mechanisms of action represent a promising strategy. As for prostate cancer and breast cancer, the two most prevalent cancer types worldwide, several combination-based therapies have been evaluated. In this review, we will provide an overview of the RT and TRT agents currently used or being investigated in combination with hormone therapy, chemotherapy, immunotherapy, and external beam radiation therapy for the treatment of prostate cancer and breast cancer.
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SPECT Imaging of SST2-Expressing Tumors with 99mTc-Based Somatostatin Receptor Antagonists: The Role of Tetraamine, HYNIC, and Spacers. Pharmaceuticals (Basel) 2021; 14:ph14040300. [PMID: 33800582 PMCID: PMC8065591 DOI: 10.3390/ph14040300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/24/2022] Open
Abstract
[99mTc]Tc-HYNIC-TOC is the most widely used 99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. 99mTc-labeled SST antagonists are lacking in clinical practice. Surprisingly, when [99mTc]Tc-HYNIC was conjugated to the SST2 antagonist SS01, SST2 imaging was not feasible. This was not the case when [99mTc]Tc-N4 was conjugated to SS01. Here, we assessed the introduction of different spacers (X: β-Ala, Ahx, Aun and PEG4) among HYNIC and SS01 with the aim of restoring the affinity of HYNIC conjugates. In addition, we used the alternative antagonist JR11 for determining the suitability of HYNIC with 99mTc-labeled SST2 antagonists. We performed a head-to-head comparison of the N4 conjugates of SS01 and JR11. [99mTc]Tc-HYNIC-TOC was used as a reference, and HEK-SST2 cells were used for in vitro and in vivo evaluation. EDDA was used as a co-ligand for all [99mTc]Tc-HYNIC conjugates. The introduction of Ahx restored, to a great extent, the SST2-mediated cellular uptake of the [99mTc]Tc-HYNIC-X conjugates (X: spacer), albeit lower than the corresponding [99mTc]Tc-N4-conjugates. SPECT/CT images showed that all 99mTc-labeled conjugates accumulated in the tumor and kidneys with [99mTc]Tc-HYNIC-PEG4-SS01, [99mTc]Tc-N4-SS01 and [99mTc]Tc-N4-JR11 having notably higher kidney uptake. Biodistribution studies showed similar or better tumor-to-non-tumor ratios for the [99mTc]Tc-HYNIC-Ahx conjugates, compared to the [99mTc]Tc-N4 counterparts. The [99mTc]Tc-HYNIC-Ahx conjugates of SS01 and JR11 were comparable to [99mTc]Tc-HYNIC-TOC as imaging agents. HYNIC is a suitable chelator for the development of 99mTc-labeled SST2 antagonists when a spacer of appropriate length, such as Ahx, is used.
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Meester EJ, de Blois E, Krenning BJ, van der Steen AFW, Norenberg JP, van Gaalen K, Bernsen MR, de Jong M, van der Heiden K. Autoradiographical assessment of inflammation-targeting radioligands for atherosclerosis imaging: potential for plaque phenotype identification. EJNMMI Res 2021; 11:27. [PMID: 33730311 PMCID: PMC7969682 DOI: 10.1186/s13550-021-00772-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 03/05/2021] [Indexed: 12/26/2022] Open
Abstract
PURPOSE Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes. METHODS Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands [111In]In-DOTATATE; [111In]In-DOTA-JR11; [67Ga]Ga-Pentixafor; [111In]In-DANBIRT; and [111In]In-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared. RESULTS In sections characterized as vulnerable plaque, binding was highest for [111In]In-EC0800; followed by [111In]In-DANBIRT; [67Ga]Ga-Pentixafor; [111In]In-DOTA-JR11; and [111In]In-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm2, respectively). Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest across plaque phenotypes, binding of [111In]In-DOTA-JR11 and [67Ga]Ga-Pentixafor differed most between plaque phenotypes. Binding of [111In]In-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand's target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections. CONCLUSIONS Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque. [111In]In-EC0800 and [111In]In-DANBIRT appear most suitable for plaque detection, while [67Ga]Ga-Pentixafor and [111In]In-DOTA-JR11 might be best suited for differentiation between plaque phenotypes.
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Affiliation(s)
- Eric J Meester
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Erik de Blois
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | | | - Antonius F W van der Steen
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Jeff P Norenberg
- Radiopharmaceutical Sciences, University of New Mexico, Albuquerque, NM, USA
| | - Kim van Gaalen
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Monique R Bernsen
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Marion de Jong
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Kim van der Heiden
- Department of Biomedical Engineering, Thorax Center, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
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Minczeles NS, Hofland J, de Herder WW, Brabander T. Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy. Curr Oncol Rep 2021; 23:46. [PMID: 33721105 PMCID: PMC7960621 DOI: 10.1007/s11912-021-01037-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. RECENT FINDINGS Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.
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Affiliation(s)
- N S Minczeles
- Department of Internal Medicine, Section of Endocrinology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, The Netherlands
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
- ENETS Center of Excellence Rotterdam, Rotterdam, The Netherlands
| | - J Hofland
- Department of Internal Medicine, Section of Endocrinology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, The Netherlands
- ENETS Center of Excellence Rotterdam, Rotterdam, The Netherlands
| | - W W de Herder
- Department of Internal Medicine, Section of Endocrinology, Erasmus MC and Erasmus MC Cancer Center, Rotterdam, The Netherlands
- ENETS Center of Excellence Rotterdam, Rotterdam, The Netherlands
| | - T Brabander
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
- ENETS Center of Excellence Rotterdam, Rotterdam, The Netherlands.
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Haider M, Das S, Al-Toubah T, Pelle E, El-Haddad G, Strosberg J. Somatostatin receptor radionuclide therapy in neuroendocrine tumors. Endocr Relat Cancer 2021; 28:R81-R93. [PMID: 33608483 PMCID: PMC8118168 DOI: 10.1530/erc-20-0360] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 12/28/2022]
Abstract
Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.
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Affiliation(s)
- Mintallah Haider
- Moffitt Cancer Center, Department of GI Oncology, Tampa, Florida, USA
| | - Satya Das
- Department of GI Oncology, Vanderbilt University, Nashville, Tennessee, USA
| | | | - Eleonora Pelle
- Department of Oncology, University of Bari, Bari, Puglia, Italy
| | - Ghassan El-Haddad
- Moffitt Cancer Center, Department of Diagnostic Imaging and Interventional Radiology, Tampa, Florida, USA
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Das S, Du L, Schad A, Jain S, Jessop A, Shah C, Eisner D, Cardin D, Ciombor K, Goff L, Bradshaw M, Delbeke D, Sandler M, Berlin J. A clinical score for neuroendocrine tumor patients under consideration for Lu-177-DOTATATE therapy. Endocr Relat Cancer 2021; 28:203-212. [PMID: 33608484 PMCID: PMC8026653 DOI: 10.1530/erc-20-0482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/11/2021] [Indexed: 01/01/2023]
Abstract
We developed a clinical score (CS) at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with progressive well-differentiated neuroendocrine tumors (NETs) receiving therapy with Lutetium-177 (177Lu)-DOTATATE. Patients under consideration for 177Lu-DOTATATE between March 1, 2016 and March 17, 2020 at VICC were assigned a CS prospectively. The CS included 5 categories: available treatments for tumor type outside of 177Lu-DOTATATE, prior systemic treatments, patient symptoms, tumor burden in critical organs and presence of peritoneal carcinomatosis. The primary outcome of the analysis was progression-free survival (PFS). To evaluate the effect of the CS on PFS, a multivariable Cox regression analysis was performed adjusting for tumor grade, primary tumor location, and the interaction between 177Lu-DOTATATE doses received (zero, 1-2, 3-4) and CS. A total of 91 patients and 31 patients received 3-4 doses and zero doses of 177Lu-DOTATATE, respectively. On multivariable analysis, in patients treated with 3-4 doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated hazard ratio (HR) for PFS was 2.0 (95% CI 1.61-2.48). On multivariable analysis, in patients who received zero doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated HR for PFS was 1.22 (95% CI 0.91-1.65). Among patients treated with 3-4 doses of 177Lu-DOTATATE, those with lower CS experienced improved PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive 177Lu-DOTATATE, suggesting the predictive utility of the score.
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Affiliation(s)
- Satya Das
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
| | - Liping Du
- Vanderbilt University of Medical Center, Department of Biostatistics, Nashville, TN, USA
| | - Aimee Schad
- Rush Medical Center, Department of Medicine, Chicago, IL, USA
| | - Shikha Jain
- University of Illinois Chicago, Department of Medicine, Chicago, IL, USA
| | - Aaron Jessop
- Vanderbilt University Medical Center, Department of Radiology, Nashville, TN, USA
| | - Chirayu Shah
- Vanderbilt University Medical Center, Department of Radiology, Nashville, TN, USA
| | - David Eisner
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
| | - Dana Cardin
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
| | - Kristen Ciombor
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
| | - Laura Goff
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
| | - Marques Bradshaw
- Vanderbilt University Medical Center, Department of Radiology, Nashville, TN, USA
| | - Dominique Delbeke
- Vanderbilt University Medical Center, Department of Radiology, Nashville, TN, USA
| | - Martin Sandler
- Vanderbilt University Medical Center, Department of Radiology, Nashville, TN, USA
| | - Jordan Berlin
- Vanderbilt University Medical Center, Department of Medicine, Division of Hematology Oncology, Nashville, TN, USA
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Feijtel D, Doeswijk GN, Verkaik NS, Haeck JC, Chicco D, Angotti C, Konijnenberg MW, de Jong M, Nonnekens J. Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response. Theranostics 2021; 11:491-505. [PMID: 33391488 PMCID: PMC7738856 DOI: 10.7150/thno.51215] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/28/2020] [Indexed: 12/24/2022] Open
Abstract
Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with lutetium-177 is targeted to NET cells by binding to the somatostatin receptor subtype 2 (SST2). During radioactive decay, DNA damage is induced, leading to NET cell death. Although the therapy proves to be effective, mortality rates remain high. To appropriately select more optimal treatment strategies, it is essential to first better understand the radiobiological responses of tumor cells to PRRT. Methods: We analyzed PRRT induced radiobiological responses in SST2 expressing cells and xenografted mice using SPECT/MRI scanning and histological and molecular analyses. We measured [177Lu]Lu-DOTA-TATE uptake and performed analyses to visualize induction of DNA damage, cell death and other cellular characteristics. Results: The highest accumulation of radioactivity was measured in the tumor and kidneys. PRRT induced DNA damage signaling and repair in a time-dependent manner. We observed intra-tumor heterogeneity of DNA damage and apoptosis, which was not attributed to proliferation or bioavailability. We found a strong correlation between high DNA damage levels and high SST2 expression. PRRT elicited a different therapeutic response between models with different SST2 expression levels. Heterogeneous SST2 expression levels were also confirmed in patient NETs. Conclusion: Heterogeneous SST2 expression levels within NETs cause differentially induced DNA damage levels, influence recurrent tumor phenotypes and impact the therapeutic response in different models and potentially in patients. Our results contribute to a better understanding of PRRT effects, which might impact future therapeutic outcome of NET patients.
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Moody TW, Lee L, Ramos-Alvarez I, Iordanskaia T, Mantey SA, Jensen RT. Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy. Front Endocrinol (Lausanne) 2021; 12:728088. [PMID: 34539578 PMCID: PMC8441013 DOI: 10.3389/fendo.2021.728088] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.
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Affiliation(s)
- Terry W. Moody
- Department of Health and Human Services, National Cancer Institute, Center for Cancer Training, Office of the Director, Bethesda, MD, United States
| | - Lingaku Lee
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Gastroenterology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Tatiana Iordanskaia
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Samuel A. Mantey
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Robert T. Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Robert T. Jensen,
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Hu Y, Ye Z, Wang F, Qin Y, Xu X, Yu X, Ji S. Role of Somatostatin Receptor in Pancreatic Neuroendocrine Tumor Development, Diagnosis, and Therapy. Front Endocrinol (Lausanne) 2021; 12:679000. [PMID: 34093445 PMCID: PMC8170475 DOI: 10.3389/fendo.2021.679000] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/27/2021] [Indexed: 12/02/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare and part of the diverse family of neuroendocrine neoplasms (NENs). Somatostatin receptors (SSTRs), which are widely expressed in NENs, are G-protein coupled receptors that can be activated by somatostatins or its synthetic analogs. Therefore, SSTRs have been widely researched as a diagnostic marker and therapeutic target in pNETs. A large number of studies have demonstrated the clinical significance of SSTRs in pNETs. In this review, relevant literature has been appraised to summarize the most recent empirical evidence addressing the clinical significance of SSTRs in pNETs. Overall, these studies have shown that SSTRs have great value in the diagnosis, treatment, and prognostic prediction of pNETs; however, further research is still necessary.
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Affiliation(s)
- Yuheng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Fei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- *Correspondence: Xianjun Yu, ; Shunrong Ji,
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- *Correspondence: Xianjun Yu, ; Shunrong Ji,
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