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Abstract (Maximum 200 Words) (abstract should contain no proprietary or confidential information)Vascular targeting agents (VTA) are new types of anticancer drugs that act on existing tumor vasculature, causing vascular disruption, which ultimately leads to extensive ischemic tumor cell death. Interesting findings showed that VTA killed cells predominantly in the more hypoxic tumor center, as a consequence of hemorrhagic necrosis after vascular collapse, whereas the better perfused peripheral rim was less affected. This apparently limits the effectiveness of such agents and rapid re-growth of tumor residues occurs. However, these findings suggest the possibility and promise of a combination of VTA with treatments specifically targeting the viable tumor rim. Radiation can certainly be expected to be most effective against the well-perfused and oxygenated cell populations at the peripheries of the tumors.One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation after VTA, so that we may predict response and optimize the therapy. I propose to use in vivo MRI to measure and assess physiological changes, e.g. tumor blood perfusion and dynamic tissue oxygenation, in the tumors before and after treatment. I believe non-invasive MRI approaches may provide a valuable prognostic tool to predict the response of specific breast tumors to VTA.
Introduction:Targeting tumor vasculature promises effective cancer therapy (1, 2). It avoids issues of drug delivery and is potentiated by massive downstream effects where one blood vessel may supply the nutrients for thousands of tumor cells. Thus, disrupting the vascular supply should generate magnified tumor cell kill. Thus, inhibiting the growth of new blood vessels, i.e., antiangiogenesis, should prevent growth and metastasis of the primary tumor (1, 2). In addition to the focus on the antiangiogenic approaches, vascular targeting, directly attacking the existing neovasculature, is an alternative strategy against the tumor blood vessel network. Tubulin binding agents, e.g., combretastatin A-4-phosphate (CA4P) represent one kind of vascular targeting agent (VTA) (3-5). Promising preclinical studies have shown that such agents selectively cause tumor vascular shutdown and subsequently trigger a cascade of tumor cell death in experimental tumors (4-6). However, survived tissues in a thin viable rim of tumor usually re-grow ...