@article{d5544f0ab0ec44aabfbcff5669ae5102,
title = "Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms",
abstract = "Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient{\textquoteright}s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.",
keywords = "3D cell culture, ATM, DNA damage response, chemoradiotherapy, colorectal cancer, patient-derived organoid, proton radiation, translational radio-oncology",
author = "Kristin Pape and L{\"o}{\ss}ner, {Anna J.} and Doreen William and Tabea Czempiel and Elke Beyreuther and Anna Klimova and Claudia Lehmann and Tim Schm{\"a}che and Merker, {Sebastian R.} and Max Naumann and Ada, {Anne Marlen} and Franziska Baenke and Therese Seidlitz and Rebecca B{\"u}tof and Antje Dietrich and Mechthild Krause and J{\"u}rgen Weitz and Barbara Klink and {von Neubeck}, Cl{\"a}re and Stange, {Daniel E.}",
note = "Funding Information: This research was funded by the Kosing Stiftung, Deutsche Krebshilfe (#70113745), Wilhelm Sander-Stiftung (2014.104.1), Hector Stiftung (M65.2), and European Union{\textquoteright}s Horizon 2020 research and innovation program (730983, INSPIRE). Funding Information: In the past five years, Mechthild Krause received funding for her research projects by Merck KGaA (2014–2018 for preclinical study; 2018–2020 for clinical study) and Medipan GmbH (2014–2018). She is involved in an ongoing, publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan, Attomol GmbH, GA Generic Assays GmbH, Gesellschaft f{\"u}r medizinische und wissenschaftliche genetische Analysen, Lipotype GmbH, and PolyAn GmbH. For the present study, Mechthild Krause confirms that none of the above-mentioned funding sources were involved. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Publisher Copyright: {\textcopyright} 2022 by the authors.",
year = "2022",
month = oct,
day = "11",
doi = "10.3390/cancers14204984",
language = "English",
volume = "14",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "20",
}