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Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma is a devastating disease. Using modern technique of radiotherapy, such as proton therapy, may simultaneously enhance dose to the tumor and decrease dose to surrounding organ, thus limiting toxicity. Moreover, associating drugs to radiotherapy also inc...

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Autores principales: Waissi, Waisse, Nicol, Anaïs, Jung, Matthieu, Rousseau, Marc, Jarnet, Delphine, Noel, Georges, Burckel, Hélène
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866541/
https://www.ncbi.nlm.nih.gov/pubmed/33573176
http://dx.doi.org/10.3390/cancers13030527
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author Waissi, Waisse
Nicol, Anaïs
Jung, Matthieu
Rousseau, Marc
Jarnet, Delphine
Noel, Georges
Burckel, Hélène
author_facet Waissi, Waisse
Nicol, Anaïs
Jung, Matthieu
Rousseau, Marc
Jarnet, Delphine
Noel, Georges
Burckel, Hélène
author_sort Waissi, Waisse
collection PubMed
description SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma is a devastating disease. Using modern technique of radiotherapy, such as proton therapy, may simultaneously enhance dose to the tumor and decrease dose to surrounding organ, thus limiting toxicity. Moreover, associating drugs to radiotherapy also increases its effectiveness on tumor. The aim of our study was to show the benefit of proton therapy compared to standard radiotherapy with photon, and the benefit of associating different drugs with those particles in vivo. Thus, our results displayed a higher effectiveness of associating proton therapy, gemcitabine and olaparib. Finally, we pointed out that treatment induced significant transcriptomic alterations. ABSTRACT: Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.
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spelling pubmed-78665412021-02-07 Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation Waissi, Waisse Nicol, Anaïs Jung, Matthieu Rousseau, Marc Jarnet, Delphine Noel, Georges Burckel, Hélène Cancers (Basel) Article SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma is a devastating disease. Using modern technique of radiotherapy, such as proton therapy, may simultaneously enhance dose to the tumor and decrease dose to surrounding organ, thus limiting toxicity. Moreover, associating drugs to radiotherapy also increases its effectiveness on tumor. The aim of our study was to show the benefit of proton therapy compared to standard radiotherapy with photon, and the benefit of associating different drugs with those particles in vivo. Thus, our results displayed a higher effectiveness of associating proton therapy, gemcitabine and olaparib. Finally, we pointed out that treatment induced significant transcriptomic alterations. ABSTRACT: Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response. MDPI 2021-01-30 /pmc/articles/PMC7866541/ /pubmed/33573176 http://dx.doi.org/10.3390/cancers13030527 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Waissi, Waisse
Nicol, Anaïs
Jung, Matthieu
Rousseau, Marc
Jarnet, Delphine
Noel, Georges
Burckel, Hélène
Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title_full Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title_fullStr Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title_full_unstemmed Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title_short Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
title_sort radiosensitizing pancreatic cancer with parp inhibitor and gemcitabine: an in vivo and a whole-transcriptome analysis after proton or photon irradiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866541/
https://www.ncbi.nlm.nih.gov/pubmed/33573176
http://dx.doi.org/10.3390/cancers13030527
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