Patient-derived pancreatic cancer organoids as a personalized preclinical tool for drug response prediction

Given the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) there is an urgent need for personalized therapeutic strategies in order to improve survival. A promising approach is a culture set-up of organoids generated from tumor tissue that enables specific drug testing and the development of individualized treatment regimens. Organoids are three-dimensional cultures derived from tissue specific stem cells with the capacity to self-organize into structures that recapitulate features of tissue architecture and function found in vivo . We recently demonstrated that patient-derived xenograft tumor (PDX) and corresponding PDX-derived organoids show high concordance on a morphological, immunohistochemical and deep molecular profiling level concluding that patient-derived organoids (PDOs) may represent a feasible approach to predict drug response. Tissue samples for generation of PDOs were acquired by means of ultrasound-guided biopsy of the primary tumor and its metastases, EUS (endoscopic ultrasound)-guided fine needle biopsy and surgical resection. PDOs from more than 30 treatment-naïve and pretreated PDAC patients were successfully isolated and expanded with a satisfying PDO generation efficiency above 75%. To evaluate drug response of standard-of-care chemotherapeutics, a viability assay was used to calculate the cell death ratio (dead cells upon drug treatment/dead cells upon vehicle treatment) reflecting the cytotoxic effect. Repetition of standardized drug screens confirmed the robustness of our method. Drug-dose response tests with ten different dosages covering two orders of magnitude allowed us to calculate the AUC (area under the curve) and to cluster in vitro response for each drug. PDOs exhibited heterogeneous responses to standard-of-care substances and PDO drug prediction profiles paralleled the observed patient response. Thus, we present a feasible preclinical tool for drug response prediction to pave the way towards an organoid-based precision medicine in clinical routine. Publication History Article published online: 08 September 2020 © Georg Thieme Verlag KG Stuttgart · New York