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