A Simple Three-dimensional Hydrogel Platform Enables Ex Vivo Cell Culture of Patient and PDX Tumors for Assaying Their Response to Clinically Relevant Therapies

摘要

A cell culture platform that enables ex vivo tissue growth from patients or patient-derived xenograft (PDX) models and assesses sensitivity to approved therapies (e.g., temozolomide) in a clinically relevant time frame would be very useful in translational research and personalized medicine. Here, we present a novel three-dimensional (3D) ECM hydrogel system, VersaGel, for assaying ex vivo growth and therapeutic response with standard image microscopy. Specifically, multicellular spheroids deriving from either 5 patients with glioblastoma (GBM) or a renal cell carcinoma (RCC) PDX model were incorporated into VersaGel and treated with temozolomide and several other therapies, guided by the most recent advances in GBM treatment. RCC ex vivo tissue displayed invasive phenotypes in conditioned media. For the GBM patient tumor testing, all five clinical responses were predicted by the results of our 3D-temozolomide assay. In contrast, the MTT assay found no response to temozolomide regardless of the clinical outcome, and moreover, basement membrane extract failed to predict the 2 patient responders. Finally, 1 patient was tested with repurposed drugs currently being administered in GBM clinical trials. Interestingly, IC(50)s were lower than C-max for crizotinib and chloroquine, but higher for sorafenib. In conclusion, a novel hydrogel platform, VersaGel, enables ex vivo tumor growth of patient and PDX tissue and offers insight into patient response to clinically relevant therapies. We propose a novel 3D hydrogel platform, VersaGel, to grow ex vivo tissue (patient and PDX) and assay therapeutic response using time-course image analysis.