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Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-...

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Autores principales: Roger, Elodie, Gout, Johann, Arnold, Frank, Beutel, Alica K., Müller, Martin, Abaei, Alireza, Barth, Thomas F. E., Rasche, Volker, Seufferlein, Thomas, Perkhofer, Lukas, Kleger, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563330/
https://www.ncbi.nlm.nih.gov/pubmed/32948057
http://dx.doi.org/10.3390/cells9092110
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author Roger, Elodie
Gout, Johann
Arnold, Frank
Beutel, Alica K.
Müller, Martin
Abaei, Alireza
Barth, Thomas F. E.
Rasche, Volker
Seufferlein, Thomas
Perkhofer, Lukas
Kleger, Alexander
author_facet Roger, Elodie
Gout, Johann
Arnold, Frank
Beutel, Alica K.
Müller, Martin
Abaei, Alireza
Barth, Thomas F. E.
Rasche, Volker
Seufferlein, Thomas
Perkhofer, Lukas
Kleger, Alexander
author_sort Roger, Elodie
collection PubMed
description Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC.
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spelling pubmed-75633302020-10-27 Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy Roger, Elodie Gout, Johann Arnold, Frank Beutel, Alica K. Müller, Martin Abaei, Alireza Barth, Thomas F. E. Rasche, Volker Seufferlein, Thomas Perkhofer, Lukas Kleger, Alexander Cells Article Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC. MDPI 2020-09-16 /pmc/articles/PMC7563330/ /pubmed/32948057 http://dx.doi.org/10.3390/cells9092110 Text en © 2020 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
Roger, Elodie
Gout, Johann
Arnold, Frank
Beutel, Alica K.
Müller, Martin
Abaei, Alireza
Barth, Thomas F. E.
Rasche, Volker
Seufferlein, Thomas
Perkhofer, Lukas
Kleger, Alexander
Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title_full Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title_fullStr Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title_full_unstemmed Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title_short Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy
title_sort maintenance therapy for atm-deficient pancreatic cancer by multiple dna damage response interferences after platinum-based chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563330/
https://www.ncbi.nlm.nih.gov/pubmed/32948057
http://dx.doi.org/10.3390/cells9092110
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