Treatment strategies are stratified by risk factors; a goal of stratification into different prognostic groups is to[unreadable] design risk based treatment strategies. Long term survival is determined by "risk factors" that predict[unreadable] prognostic parameters such as probability of local control and risk of developing systemic or metastatic[unreadable] disease. Tumor hypoxia is predictive of both risk of metastases and aggressive local disease. A[unreadable] non-invasive assay to measure hypoxia would provide prognostic information regarding local tumor[unreadable] aggressiveness and metastatic risk for development of risk based therapy, and for monitoring changes in[unreadable] oxygenation with treatment, could impact further therapy. The central hypothesis of this proposal is that[unreadable] tumor hypoxia and changes in oxygenation can be evaluated non-invasively using selected surrogate[unreadable] "markers". In all studies, we will utilize a stereotaxic template we have developed to register both the in[unreadable] vivo data and the p02 and pimonidazole studies. In Aim 1 we will test and validate a novel derivative of[unreadable] misonidazole (trifluoromisonidazole (T19F-FMISO)) for imaging hypoxia. We will determine the optimal[unreadable] dose as a balance between signal to noise requirements vs. specificity for imaging hypoxia, and also[unreadable] compare to 18F-misonidazole and p02. In Aim 2 we will evaluate quantitation of lactate, dynamic contrast[unreadable] enhanced MRI, andT19F-FMISO as oxygen surrogates and validate them against p02 and pimonidazole.[unreadable] In Aim 2B, we will study changes in hypoxia induced by anti-neoplastic therapy and use these[unreadable] measurements as potential surrogate and compare to p02, microvessel density and radiobiological assays.[unreadable] The goal of Aim 2 is to determine which is the best surrogate of hypoxia and apply this in Aim 3. Aim 3 will[unreadable] use this data to optimize hypoxia driven suicide gene therapy. In aim 3, we will develop a fusion suicide[unreadable] gene (Cytosine Deaminase - Uracil Phosphoribosyl Transferase - CD-UPRT), under the control of a[unreadable] hypoxia response element (HRE) which can be quantitatively imaged by 19F NMR chemical shift imaging.[unreadable] We will develop this system as a both a reporter and suicide therapy system and evaluate its efficacy and[unreadable] compare it with thymidine kinase in parallel studies.[unreadable]
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NIH ExPorter