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PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer
BACKGROUND: Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibi...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9474773/ https://www.ncbi.nlm.nih.gov/pubmed/36104637 http://dx.doi.org/10.1186/s13550-022-00932-9 |
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author | Ambur Sankaranarayanan, Ramya Florea, Alexandru Allekotte, Susanne Vogg, Andreas T. J. Maurer, Jochen Schäfer, Laura Bolm, Carsten Terhorst, Steven Classen, Arno Bauwens, Matthias Morgenroth, Agnieszka Mottaghy, Felix M. |
author_facet | Ambur Sankaranarayanan, Ramya Florea, Alexandru Allekotte, Susanne Vogg, Andreas T. J. Maurer, Jochen Schäfer, Laura Bolm, Carsten Terhorst, Steven Classen, Arno Bauwens, Matthias Morgenroth, Agnieszka Mottaghy, Felix M. |
author_sort | Ambur Sankaranarayanan, Ramya |
collection | PubMed |
description | BACKGROUND: Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCA(mut)). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters (123/125)I. METHODS: TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm(3), [(123)I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [(125)I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. RESULTS: SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [(125)I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. CONCLUSION: Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [(125)I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00932-9. |
format | Online Article Text |
id | pubmed-9474773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-94747732022-09-16 PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer Ambur Sankaranarayanan, Ramya Florea, Alexandru Allekotte, Susanne Vogg, Andreas T. J. Maurer, Jochen Schäfer, Laura Bolm, Carsten Terhorst, Steven Classen, Arno Bauwens, Matthias Morgenroth, Agnieszka Mottaghy, Felix M. EJNMMI Res Original Research BACKGROUND: Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCA(mut)). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters (123/125)I. METHODS: TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm(3), [(123)I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [(125)I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. RESULTS: SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [(125)I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. CONCLUSION: Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [(125)I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00932-9. Springer Berlin Heidelberg 2022-09-14 /pmc/articles/PMC9474773/ /pubmed/36104637 http://dx.doi.org/10.1186/s13550-022-00932-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Research Ambur Sankaranarayanan, Ramya Florea, Alexandru Allekotte, Susanne Vogg, Andreas T. J. Maurer, Jochen Schäfer, Laura Bolm, Carsten Terhorst, Steven Classen, Arno Bauwens, Matthias Morgenroth, Agnieszka Mottaghy, Felix M. PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title | PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title_full | PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title_fullStr | PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title_full_unstemmed | PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title_short | PARP targeted Auger emitter therapy with [(125)I]PARPi-01 for triple-negative breast cancer |
title_sort | parp targeted auger emitter therapy with [(125)i]parpi-01 for triple-negative breast cancer |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9474773/ https://www.ncbi.nlm.nih.gov/pubmed/36104637 http://dx.doi.org/10.1186/s13550-022-00932-9 |
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