Malignant gliomas present great difficulties in treatment, with little change over the past 25 years in the median survival time of 12 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments), or destroying formed tumor vasculature (vascular disrupting agents) show promise. This application will use magnetic resonance (MR) contrast agents (CAs) and MR detection to measure blood volume, the blood-to-brain transvascular transfer constant, the extravascular extracellular space, and the total extracellular space in cerebral tumors, and also to measure tumor blood flow using MR arterial spin tagging. These parameters present an important summary of the physiology of vasculature, both normal and tumorous. It is proposed to use these vascular parameters as MR biomarkers in animal models of cerebral gliomas. In a series of experiments, we will examine the change in MR-measured vascular parameters after antiangiogenic therapy, after vascular disrupting agent, and after RT, with all MR measures correlated with histopathological assessments of vascular and cellular density in the model tumors. After single-agent therapies are studied, combination therapies will be studied, and MRI vascular biomarkers will be examined as predictors of response as judged both by histopathological assessments and long-term survival. At the completion of these studies, the relation of MR-measured vascular parameters to cellular responses to single and combination therapies will be established, and the utility of MR-measured vascular parameters as predictors of long-term survival assessed. The MR-measured parameters can be translated to clinical use and evaluated as predictors of human tumor response to therapies. These studies represent a first step in a paradigm shift in cancer treatment delivery from a heuristic and formulaic approach to an individualized plan of image guided treatment and response monitoring.
The utility of quantitative MR-measured vascular parameters for predicting brain tumor response to promising anti-angiogenic agents and vascular disrupting agents applied singly or in combination with or without radiation therapy will be shown. The studies presented represent a first step in a paradigm shift in cancer treatment delivery from a one-solution-fits-all approach to an individualized plan of image guided treatment and response monitoring.
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