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Open AccessArticle

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

1
Centre Leon Bérard, Department of Radiation Oncology, 69008 Lyon, France
2
Institut de Cancérologie Strasbourg Europe (ICANS), Radiobiology Laboratory, Paul Strauss Comprehensive Cancer Center, Strasbourg University, UNICANCER, 67000 Strasbourg, France
3
Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), UdS, CNRS, INSERM, 1 rue Laurent Fries, B.P. 10142, 67404 Cedex Illkirch, France
4
Institut Pluridisciplinaire Hubert Curien, Strasbourg University, CNRS, UMR 7178, 67200 Strasbourg, France
5
Paul Strauss Comprehensive Cancer Center, Medical Physic Unit, Institut de Cancérologie Strasbourg Europe (ICANS), UNICANCER, 17 Rue Albert Calmette, 67200 Strasbourg, France
6
Institut de Cancérologie Strasbourg Europe (ICANS), Department of Radiation Oncology, Paul Strauss Comprehensive Cancer Center, UNICANCER, 17 Rue Albert Calmette, 67200 Strasbourg, France
*
Author to whom correspondence should be addressed.
Academic Editor: Hitoshi Ishikawa
Cancers 2021, 13(3), 527; https://doi.org/10.3390/cancers13030527
Received: 30 December 2020 / Revised: 26 January 2021 / Accepted: 27 January 2021 / Published: 30 January 2021
(This article belongs to the Special Issue Proton Therapy For Cancers)
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.
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. View Full-Text
Keywords: pancreatic cancer; proton therapy; radiotherapy; DNA repair; gemcitabine; PARP inhibitor; transcriptome pancreatic cancer; proton therapy; radiotherapy; DNA repair; gemcitabine; PARP inhibitor; transcriptome
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MDPI and ACS Style

Waissi, W.; Nicol, A.; Jung, M.; Rousseau, M.; Jarnet, D.; Noel, G.; Burckel, H. Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation. Cancers 2021, 13, 527. https://doi.org/10.3390/cancers13030527

AMA Style

Waissi W, Nicol A, Jung M, Rousseau M, Jarnet D, Noel G, Burckel H. Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation. Cancers. 2021; 13(3):527. https://doi.org/10.3390/cancers13030527

Chicago/Turabian Style

Waissi, Waisse; Nicol, Anaïs; Jung, Matthieu; Rousseau, Marc; Jarnet, Delphine; Noel, Georges; Burckel, Hélène. 2021. "Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation" Cancers 13, no. 3: 527. https://doi.org/10.3390/cancers13030527

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