Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases

BACKGROUND: A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide t...

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Autores principales: Dearling, Jason L. J., van Dam, Ellen M., Harris, Matthew J., Packard, Alan B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907331/
https://www.ncbi.nlm.nih.gov/pubmed/33630166
http://dx.doi.org/10.1186/s13550-021-00763-0
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author Dearling, Jason L. J.
van Dam, Ellen M.
Harris, Matthew J.
Packard, Alan B.
author_facet Dearling, Jason L. J.
van Dam, Ellen M.
Harris, Matthew J.
Packard, Alan B.
author_sort Dearling, Jason L. J.
collection PubMed
description BACKGROUND: A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [(64)Cu]Cu-SARTATE to detect and monitor the disease and [(67)Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [(64)Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [(67)Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. RESULTS: PET imaging and ex vivo biodistribution confirmed tumor uptake of [(64)Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [(64)Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [(67)Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [(67)Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). CONCLUSIONS: Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [(64/67)Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.
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spelling pubmed-79073312021-03-09 Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases Dearling, Jason L. J. van Dam, Ellen M. Harris, Matthew J. Packard, Alan B. EJNMMI Res Original Research BACKGROUND: A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [(64)Cu]Cu-SARTATE to detect and monitor the disease and [(67)Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [(64)Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [(67)Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. RESULTS: PET imaging and ex vivo biodistribution confirmed tumor uptake of [(64)Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [(64)Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [(67)Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [(67)Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). CONCLUSIONS: Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [(64/67)Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD. Springer Berlin Heidelberg 2021-02-25 /pmc/articles/PMC7907331/ /pubmed/33630166 http://dx.doi.org/10.1186/s13550-021-00763-0 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Research
Dearling, Jason L. J.
van Dam, Ellen M.
Harris, Matthew J.
Packard, Alan B.
Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title_full Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title_fullStr Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title_full_unstemmed Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title_short Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases
title_sort detection and therapy of neuroblastoma minimal residual disease using [(64/67)cu]cu-sartate in a preclinical model of hepatic metastases
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907331/
https://www.ncbi.nlm.nih.gov/pubmed/33630166
http://dx.doi.org/10.1186/s13550-021-00763-0
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