This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumor microcirculation and oxygenation play important roles in malignant progression and metastasis, as well as response to various therapies. We hypothesize that tumor hypoxia is major driving force for progression of breast cancer brain metastasis and represents a critical target for therapeutic strategies. We will establish orthotopic brain metastasis model in nude mice. Various human breast tumor cell lines will be stably transfected with hypoxia reporter system (HRE-luciferase). By applying non-invasive bioluminescence imaging (BLI) and MRI approaches, we will be able to evaluate longitudinal intracranial tumor hypoxia in vivo. MRI approach will be used to provide non-invasive monitoring of both tumor vascular and tissue oxygenation. The presence of the blood brain barrier (BBB) presents a huge challenge for effective delivery of therapeutics to brain. We have also developed a MRI approach to study BBB permeability based on dynamic contrast enhanced (DCE) MRI. We plan to apply these MRI approaches to correlating hypoxia with BBB and tumor aggressiveness of breast cancer brain metastasis on both a temporal and spatial basis. Tumor hypoxia will also be monitored non-invasively by BLI. Integration of MRI and BLI will provide temporal and spatial information of tumor hypoxia evolution. 2-Methoxyestradiol is currently in Phase I/II trials against primary breast cancer. Studies have shown that 2-methoxyestradiol is a radiation sensitizer by reducing tumor hypoxia. We hypothesize that 2-methoxyestradiol will enhance radiation response by modifying tumor hypoxia. Successful accomplishment of the goals of this project will enhance our understanding of the mechanisms of clinical breast cancer brain metastasis.
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