A malignant human glioblastoma orthotopic mouse model with opportunities for non-invasive real time ultrasound imaging

2905 Progress in understanding glioblastoma multiforme (GBM) pathobiology and developing novel therapies could be greatly accelerated with animal model systems that caricaturize human GBM and that enable tumor monitoring through noninvasive imaging in real time. We demonstrate that the invasive phenotype of GBM can be selected from established human GBM cell lines. Starting with the cell line DBTRG-05MG, we used an in vivo experimental metastasis selection method to obtain highly invasive DBM2 cells from lung metastases. Upon intracranial injection, DBM2 cells grow and invade both intra- and extra-cranially, with individual infiltrative tumor cells overexpressing the MET oncogene as visualized by immunohistochemistry. Intracranial tumor growth of DBM2 cells promotes osteolysis around the innoculum, providing a transcranial window for observing tumor growth and vascularization with high resolution micro-ultrasound (Vevo 770, VisualSonics, Inc). We also show that increased Area of the Opening (AO) of the skull is proportional to tumor growth. AO measurement by ultrasound provides an easy method to evaluate antitumor drug efficacy. We show that the geldanamycin derivative 17-AAG inhibits tumor growth and prolongs survival time in both orthotopic xenografts and lung metastases of DBM2 . We conclude that the DBM2 mouse model has invasive characteristics relevant to clinical GBM. This new model provides a valuable tool for investigating factors that modulate glioblastoma growth, assessing invasion and vascularity, and for testing novel therapeutic agents.