Combined Systemic Drug Treatment with Proton Therapy: Investigations on Patient-Derived Organoids

Max Naumann; Tabea Czempiel; Anna Jana Lößner; Kristin Pape; Elke Beyreuther; Steffen Löck; Stephan Drukewitz; Alexander Hennig; Cläre von Neubeck; Barbara Klink; Mechthild Krause; Doreen William; Daniel E Stange; Rebecca Bütof; Antje Dietrich

doi:10.3390/cancers14153781

Combined Systemic Drug Treatment with Proton Therapy: Investigations on Patient-Derived Organoids

Cancers (Basel). 2022 Aug 3;14(15):3781. doi: 10.3390/cancers14153781.

Authors

Max Naumann^{1

2}, Tabea Czempiel³, Anna Jana Lößner⁴, Kristin Pape⁴, Elke Beyreuther^{1

5}, Steffen Löck^{1

2

6

7

8}, Stephan Drukewitz^{3

9}, Alexander Hennig^{4

6}, Cläre von Neubeck^{1

7

10}, Barbara Klink^{3

11

12}, Mechthild Krause^{1

2

6

7

8}, Doreen William^{3

12}, Daniel E Stange^{4

6}, Rebecca Bütof^{1

2

6

8}, Antje Dietrich^{1

7}

Affiliations

¹ OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.
² Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
³ Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany.
⁴ Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
⁵ Institute of Radiation Physics, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany.
⁶ National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany.
⁷ German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany.
⁸ Institute of Radiooncology-OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.
⁹ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
¹⁰ Clinic for Particle Therapy, University Hospital Essen, Universität Duisburg Essen, 45147 Essen, Germany.
¹¹ Department of Genetics, Laboratoire National de Santé, 3555 Dudelange, Luxembourg.
¹² Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Technische Universität Dresden, ERN-GENTURIS, Hereditary Cancer Syndrome Center Dresden, 01307 Dresden, Germany.

Abstract

To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1^nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.

Keywords: 3D cell culture; PDAC; pancreatic cancer; patient-derived organoid; proton irradiation; radiochemotherapy; translational radiooncology.

Abstract

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