Therapeutic Vascular Targeting and Irradiation: Correlation of MRI Tissue Changes at Cellular and Molecular Levels to Optimizing Outcome

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. Research findings have shown that VTA kills cells predominantly in the more hypoxic area of the tumor, the tumor center, as a consequence of hemorrhagic necrosis after vascular collapse, whereas the better perfused peripheral rim is less affected. This limits the effectiveness of such agents, allowing rapid regrowth of tumor residues to occur. However, these findings also suggest the possibility and promise of a combination of VTA with treatments specifically targeting the viable tumor rim. Radiation can 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 one can predict the response and optimize the therapy. The authors propose to use in vivo magnetic resonance imaging (MRI) to measure and assess physiological changes (e.g., tumor blood perfusion and dynamic tissue oxygenation) in tumors before and after VTA treatment. The authors believe that noninvasive MRI approaches may provide a valuable prognostic tool for predicting the response of specific breast tumors to VTA. Based on the data of in vivo tumor perfusion and oxygenation dynamics in response to the vascular targeting agent, combretastatin A-4-phosphate (CA4P) evaluated by MRI, the authors successfully designed a scheme to combine the radiation treatment and CA4P to treat breast tumors. This is the major goal of the proposed project. Moreover, the pathophysiological information will be especially useful for designing a complicated scheme, which usually involves a combination of fractionated radiation and multiple doses of systemic chemotherapy at clinical settings.
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