Assays and screens; disease models

A 3-D culture system that mimics brain tissue could be used to model drug resistance in glioblastoma multiforme and screen therapies. The system involves culturing human GBM cell lines in a 3-D hydrogel composed of three conjugated components that mimic the tumor microenvironment: polyethylene glycol (PEG) for stiffness; an RGD peptide that interacts with cellular integrins; and the brain ECM component hyaluronic acid. In a human GBM cell line cultured with the hydrogel system, treatment with the epidermal growth factor receptor (EGFR; ErbB1; HER1) inhibitor Tarceva erlotinib recapitulated the development of drug resistance observed in a Tarceva-treated xenograft mouse model of GBM derived from the same cell line, whereas the cell line cultured as gliomaspheres and treated with Tarceva did not develop Tarceva resistance. Also in the Tarceva-treated GBM hydrogel culture, CD44-targeting shRNA encoded in a lentiviral vector delayed the development of erlotinib resistance compared with no treatment. Next steps could include using the 3-D hydrogel culture system to screen GBM therapies...