OpenTox Virtual Conference 2023

A predictive multi-organ-chip platform for cancer precision medicine using automated high-content substance testing

Since cancer is a condition that greatly varies between individuals, there is no universal approach of treatment. Patient-derived tumor models are already being developed to enable personalized drug treatments. However, patient-specific modelling of drug metabolization needs more complex test systems that can combine different organ models. Microphysiological systems (MPS) offer a possible solution for this obstacle, as they can emulate the interconnected human physiology. To allow for the necessary standardization and throughput necessary for patient testing, systems are needed that enable highly standardized automated handling of MPS. Here we use the HUMIMIC AutoLab to test drug treatment on human cancers. This system is a powerful automatization tool that allows handling of 24 multi-organ-chips 24/7 including continuous fluorescent and brightfield imaging. To demonstrate the methodology, two different cancer types were investigated: Patient derived gastric tumor organoids and diffuse large B cell lymphoma cell lines. To test the individual responses to chemotherapeutic prodrugs, a co-culture of each tumor model with a 3D liver spheroid model composed of HepaRG and human hepatic stellate cells for drug metabolism was established in a multi-organ-chip. Morphologic, metabolic and immunohistochemical analysis showed that the co-cultures were stable in the multi-organ-chip for at least 7 days. For the gastric cancers, the data showed effectiveness of two 5-Flourouarcil prodrugs, Tegafur and Capecitabine, commonly used in the therapy of gastric cancer, indicating biotransformation of the prodrug to their toxic metabolites via the liver model. This resulted in a significantly decrease in the gastric cancer biomass of two individual patients. For the diffuse large B-cell lymphoma cell lines, data showed varying sensitivities of the cells when treated with biotransformed Cyclophosphamide, dependent on the original cancer subtype and genetic background of the patient. The individual results of chemotherapy treatments create a path for combination and novel therapies, resulting in prognoses that are more precise and subsequently increases individual patients’ treatment success.