Treatment strategies are stratified by risk factors; a goal of stratification into different prognostic groups is to? design risk based treatment strategies. Long term survival is determined by """"""""risk factors"""""""" that predict? prognostic parameters such as probability of local control and risk of developing systemic or metastatic? disease. Tumor hypoxia is predictive of both risk of metastases and aggressive local disease. A? non-invasive assay to measure hypoxia would provide prognostic information regarding local tumor? aggressiveness and metastatic risk for development of risk based therapy, and for monitoring changes in? oxygenation with treatment, could impact further therapy. The central hypothesis of this proposal is that? tumor 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 in? vivo data and the p02 and pimonidazole studies.
In Aim 1 we will test and validate a novel derivative of? misonidazole (trifluoromisonidazole (T19F-FMISO)) for imaging hypoxia. We will determine the optimal? dose as a balance between signal to noise requirements vs. specificity for imaging hypoxia, and also? compare to 18F-misonidazole and p02.
In Aim 2 we will evaluate quantitation of lactate, dynamic contrast? enhanced MRI, andT19F-FMISO as oxygen surrogates and validate them against p02 and pimonidazole.? In Aim 2B, we will study changes in hypoxia induced by anti-neoplastic therapy and use these? measurements 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 will? use this data to optimize hypoxia driven suicide gene therapy.
In aim 3, we will develop a fusion suicide? gene (Cytosine Deaminase - Uracil Phosphoribosyl Transferase - CD-UPRT), under the control of a? hypoxia 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 and? compare it with thymidine kinase in parallel studies.?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA115675-03
Application #
7611977
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$403,509
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Leftin, Avigdor; Koutcher, Jason A (2018) Quantification of Nanoparticle Enhancement in Polarized Breast Tumor Macrophage Deposits by Spatial Analysis of MRI and Histological Iron Contrast Using Computer Vision. Contrast Media Mol Imaging 2018:3526438
Dong, Jun; Ren, Yufeng; Zhang, Tian et al. (2018) Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair. Oncol Rep 39:912-920
Dong, Jun; Zhang, Tian; Ren, Yufeng et al. (2017) Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks. Oncotarget 8:22662-22673
Leftin, Avigdor; Zhao, Huiyong; Turkekul, Mesru et al. (2017) Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. Sci Rep 7:11632
Zanzonico, Pat B (2016) The Neglected Side of the Coin: Quantitative Benefit-risk Analyses in Medical Imaging. Health Phys 110:301-4
Shaffer, Travis M; Harmsen, Stefan; Khwaja, Emaad et al. (2016) Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper-64. Nano Lett 16:5601-4
Simões, Rui V; Serganova, Inna S; Kruchevsky, Natalia et al. (2015) Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment. Neoplasia 17:671-84
Sun, Xiaorong; Ackerstaff, Ellen; He, Fuqiu et al. (2015) Visualizing the antivascular effect of bortezomib on the hypoxic tumor microenvironment. Oncotarget 6:34732-44
Shaffer, Travis M; Wall, Matthew A; Harmsen, Stefan et al. (2015) Silica nanoparticles as substrates for chelator-free labeling of oxophilic radioisotopes. Nano Lett 15:864-8
Hsiao, Hung Tsung; Xing, Ligang; Deng, Xuelong et al. (2014) Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells. Oncol Rep 32:723-9

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