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

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 Foxn1nu/nu mice. We found a mutational pattern con-
taining 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.