This research seeks to demonstrate and validate exogenous agent susceptibility and other intrinsic NMR contrast mechanisms for the in vivo assessment of active tumor neovascularity and the response to anti-angiogenic therapy. During the current funding cycle, we have demonstrated our ability to produce maps of cerebral blood volume (CBV) in humans. Using our understanding of susceptibility contrast mechanisms, developed in concert with Project 3 of this PPG, our data now support the hypotheses previously proposed that maps of brain and tumor blood volume can be generated, and that these maps are highly correlated with tumor malignancy, metabolic activity and ultimate clinical outcome. While these results are consistent with recent data on the role of tumor angiogenesis on tumor growth, simple maps of regional CBV, while promising, leave many of the most interesting questions regarding the non-invasive assessment of tumor microvascular proliferation unanswered. For example, recent post mortem and in-vivo animal work has demonstrated that the tumor vascular bed is characterized by significant changes in vessel morphology and physiology. Using first pass and equilibrium contrast agent approaches, mismatches in CBV and blood flow (FBF) in abnormal vessels will be assessed. Combined with novel MR measures of vessel size and density (developed in concert with Project 3), and MR techniques sensitive to the vascular endothelial permeability and tumor cell volume fraction developed concurrently during the previous funding cycle, a more complete picture of tumor angiogenesis will be obtained. The approach will be validated in animal cancer models of new vessel growth using vascular staining and casting techniques along with quantitative autoradiography. These techniques will also be applied to humans with gliomas, validated using PET and stereotactic biopsy quantitative histology, and applied to the problem of surveillance for malignant dedifferention. In addition, these techniques will be used to study the direct physiological consequences of treatment with the promising new class of therapeutics, the anti-angiogenic agents, and their role in monitoring therapeutic effect will be evaluated in animal models and in a pilot human trial Such studies are especially relevant in humans where little direct data on mechanism of action for these drugs exists. By providing a quantitative regional picture of the tumor microvascular bed, this research should enhance the characterization of tumors and choice of therapies in patients with brain and other systemic cancers.
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