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The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts

PURPOSE: (177)Lu-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of (177)Lu-DOTATATE. Consequently, the ai...

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Autores principales: Lundsten, Sara, Spiegelberg, Diana, Raval, Nakul R., Nestor, Marika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075859/
https://www.ncbi.nlm.nih.gov/pubmed/31912256
http://dx.doi.org/10.1007/s00259-019-04673-1
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author Lundsten, Sara
Spiegelberg, Diana
Raval, Nakul R.
Nestor, Marika
author_facet Lundsten, Sara
Spiegelberg, Diana
Raval, Nakul R.
Nestor, Marika
author_sort Lundsten, Sara
collection PubMed
description PURPOSE: (177)Lu-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of (177)Lu-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with (177)Lu-DOTATATE in vivo and to examine the toxicity profiles of the treatments. METHODS: (177)Lu-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with (177)Lu-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles. RESULTS: Biodistribution and autoradiography confirmed the SSTR-selective tumor uptake of (177)Lu-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and (177)Lu-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from (177)Lu-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the (177)Lu-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys. CONCLUSION: Treatment with Onalespib potentiated (177)Lu-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib’s radiosensitizing properties with (177)Lu-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00259-019-04673-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-70758592020-03-23 The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts Lundsten, Sara Spiegelberg, Diana Raval, Nakul R. Nestor, Marika Eur J Nucl Med Mol Imaging Original Article PURPOSE: (177)Lu-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of (177)Lu-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with (177)Lu-DOTATATE in vivo and to examine the toxicity profiles of the treatments. METHODS: (177)Lu-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with (177)Lu-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles. RESULTS: Biodistribution and autoradiography confirmed the SSTR-selective tumor uptake of (177)Lu-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and (177)Lu-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from (177)Lu-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the (177)Lu-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys. CONCLUSION: Treatment with Onalespib potentiated (177)Lu-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib’s radiosensitizing properties with (177)Lu-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00259-019-04673-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-01-07 2020 /pmc/articles/PMC7075859/ /pubmed/31912256 http://dx.doi.org/10.1007/s00259-019-04673-1 Text en © The Author(s) 2020 Open Access This 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 Article
Lundsten, Sara
Spiegelberg, Diana
Raval, Nakul R.
Nestor, Marika
The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title_full The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title_fullStr The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title_full_unstemmed The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title_short The radiosensitizer Onalespib increases complete remission in (177)Lu-DOTATATE-treated mice bearing neuroendocrine tumor xenografts
title_sort radiosensitizer onalespib increases complete remission in (177)lu-dotatate-treated mice bearing neuroendocrine tumor xenografts
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075859/
https://www.ncbi.nlm.nih.gov/pubmed/31912256
http://dx.doi.org/10.1007/s00259-019-04673-1
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