Tumor survival, growth and metastasis depend critically on the development of new blood vessels, which is called angiogenesis. Therefore, extensive research has been focused on developing strategies to suppress angiogenesis. In addition to anti-angiogenic approaches, targeting and compromising the function of the existing neovasculature using vascular targeting agents (VTA) has become an alternative strategy for attacking tumor vasculature. Despite promising results achieved by VTA alone, causing vascular shutdown and subsequently triggering a cascade of tumor cell death in experimental sarcomas, mammary carcinomas, and colorectal adenocarcinomas, tumor cells in some regions within the tumor survived, from which the tumor could regrow. Interestingly, tumor cells surviving the treatment with VTA were found to be predominantly located in the tumor periphery. The peripheral regions adjacent to normal tissues are likely to be well perfused and oxygenated. This observation suggests the feasibility of a novel therapeutic approach using a combination of vascular targeting therapy (VTT) with radiotherapy (RT), which can ideally kill the poorly oxygenated tumor center by VTA, while attacking the well-oxygenated and hence, radiosensitive rim by irradiation. I propose to evaluate this combined therapeutic approach on diverse breast tumor sublines with different degrees of aggressiveness. One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation after VTT, so that we may predict response and optimize the therapy. I propose to use diverse magnetic resonance imaging (MRI) approaches to measure and assess changes in the tumors in vivo before and after treatment. These are particularly efficient approaches, minimizing the number of animals required for the investigations and providing continuous measurements over hours. In our research group, a novel noninvasive technique has been developed to detect oxygen by using 19F magnetic resonance spectroscopy and imaging of a sensor molecule, which allows measurement of tumor oxygenation in vivo. Combined with other MRI techniques such as dynamic contrast-enhanced (DCE) MR and blood oxygen level-dependent (BOLD) MR, also correlating with cellular and molecular biology, I believe these noninvasive MRI approaches may provide a valuable prognostic tool to predict the response of specific breast tumors to VTT. While there has been great progress in the detection of breast cancer, particularly from increased public awareness and widespread mammography, and many new therapeutic modalities are available (e.g., radio-immunoconjugates, radiosensitizer, neutron therapy), prognosis remains difficult. A major goal toward conquering the disease and improving quality of life must be identifying how a given patient/tumor will respond to therapy and optimally tailoring the therapy to the characteristics of each tumor. This research seeks to develop enhanced therapy based on Prognostic Radiology. Successful accomplishment of the goals of this project will allow us to confirm the potential of this new therapeutic approach to breast cancers, and understand the vascular dynamics as well as underlining mechanisms in breast tumors in response to VTA, to optimize the novel therapy for individual breast cancers. This will lay the foundation for future clinical trials and promises a highly effective novel therapy.