Experimental Mouse Glioma to Study Novel Inhibitors of Tumor Growth

Glioblastomas (GBM) are highly chemoresistant, angiogenic andinvasive tumors. Several treatments have failed to alter patient survivals beyond 12 months of diagnosis. We hypothesize that flavopiridol, a novel cyclin dependent kinase (CDK) inhibitor, would be a promising drug treatment for GBM due to its dual capacity to deplete cells of cyclin D1, an important co-factor for CDK4 activation and cell cycle arrest, and to deplete cells of hypoxia-inducible factor-1a (HIF-1a), a protein up-regulated in response to hypoxia promoting bloodvessel formation. Over 80% of adult GBM show inactivation of the Rb tumor suppressor pathway due to overexpression of cyclin D1, mutationsin the Rb gene or loss of the negative regulator p161NK4a. In addition, HIF-1a expression in GBM is significantly associated with density of blood vessels within a tumor and tumor grade. Blood vesselformation or angiogenesis is a critical step required for sustained growth and progression of GBM. We have developed an experimental mouseglioma model which demonstrates distinct stages of tumor growth and neovascularization, including an identical expression pattern of HIF 1a as in human GBM. We demonstrate that high resolution contrast enhanced perfusion micro magnetic resonance imaging (mMRI) canbe used to monitor the efficacy of potential drugs tested in the GL261 animal model on tumor growth and angiogenic activity. The broad objectiveof this proposal will be to screen novel inhibitors of GBM growth using the experimental mouse glioma GL261 intracranial animal model.