Patients with brain tumors are in desperate need of new therapies. Recent clinical studies combining anti- angiogenic agents with conventional therapies have shown significant improvements in patient response leading to the first FDA-approved anti-angiogenic agents. Yet, to fully realize the promise of combined therapies, we need non-invasive methods that can answer critical questions about how these agents work and how to combine them optimally. Thus, the overall goal of this research, which is to develop and validate DSC (dynamic susceptibility contrast) MRI methods to monitor tumor angiogenesis and vascular normalization, is quite relevant and timely. We have characterized susceptibility-based biophysical relationships in tumors and developed a GE-SE (gradient-echo/spin-echo) method, with contrast-leakage correction, to provide measures of total (GE) and microvascular (SE) cerebral blood volume (CBV), mean vessel diameter (mVD) cerebral blood flow (CBF), and mean transit time (MTT). We have shown these to correlate with tumor grade, guide intraoperative diagnosis and distinguish radiation effects from tumor recurrence. We demonstrated a dose-dependent response to anti-angiogenic therapy in rat brain tumors, and an effect suggestive of vascular normalization, which may explain the success of combined therapies.
The specific aims are logical and exciting extensions of this work. We will continue to characterize and validate the accuracy of susceptibility contrast agent methods i. by comparing MRI and microscopy measures of CBV and mVD in rat brain tumor models and ii. by using a novel tumor-specific DSC simulation model developed by us (Aim 1). The ability of DSC methods to identify vascular normalization, and thus optimize treatment timing, will be determined with combined anti-angiogenic and radiation therapy studies in animals (Aim 2). Translation of the leakage-corrected GE/SE results to a wider scientific and clinical audience requires the comparison of our approach to other acquisition and analysis methods (Aim 3). Finally, the utility of multiparameter DSC methods to predict survival and track response to anti-angiogenic therapies will be tested in patients (Aim 4). Thus, completion of this study should improve the application and interpretation of DSC methods for the evaluation of tumor angiogenesis and combined therapeutic strategies so that it will ultimately be accepted into routine clinical practice for the benefit of brain tumor patients.
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