Effective treatment of human brain tumors poses a major challenge. One of the underlying problems is lack of reliable, noninvasive means of assessing tumor malignancy and of assessing treatment response. The current proposal aims to develop and evaluate a new, noninvasive method of assessing tumor activity based upon quantitative, statistical measures of vessel shape determined from magnetic resonance angiograms (MRA). Although we are simultaneously pursuing this approach in human subjects, there are many issues that cannot be readily addressed in human patients since whole-brain histological information is not available. This proposal employs two genetically engineered mouse models in which tumors reliably arise cte novo, in the appropriate anatomical location, with appropriate histology, and with a predictable time course. One model is a glioma that progresses from no tumor to low-grade glioma to grade 3 glioma to glioblastoma. The second model is a heavily vascular choroid plexus carcinoma that mimics the growth of metastatic tumors by producing microscopic foci of malignancy that subsequently grow to large size. This proposal aims to develop and test the proposed method of tumor activity assessment so as: a) to determine whether the new approach can both correctly classify changing tumor grade and predict tumor treatment response under both anti-angiogenic and more generic therapy, b) to compare the ability of the new method to that of more traditional imaging assessment techniques including measurement of tumor volume, perfusion imaging, and permeability imaging, and c) to determine if vessel shape abnormalities as perceived by MRA can be correlated with cancer-induced changes to the vessel wall as evaluated by histology. This proposal addresses a major clinical problem that has been highly refractory to solution by traditional methods. At the same time, the proposed work also addresses important biological questions that could lead to insights into mechanisms of tumor growth. The long term potential of the proposed work includes not only improved means of early clinical evaluation of tumor treatment, but also new methods of developing and testing therapeutic agents in both preclinical animal models and human subjects.
