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

SIMPLE SUMMARY: Radiotherapy is part of the standard of care for many solid tumors. In pancreatic ductal adenocarcinoma (PDAC), good responses to radiotherapy can only be observed in a minority of patients. In our study, we used PDAC patient-derived organoids (PDO) to investigate alternative radiotherapy approaches for PDAC, such as proton irradiation and combined radiochemotherapy (RCT). Although only very distinct differences in treatment response could be identified, we show the utility of PDOs in translational proton research and found synergistic effects of combined treatments with chemotherapy and proton irradiation in individual PDOs. 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.