This proposal is being submitted as a companion grant to our application 2R01 CA109106 which was reviewed by the BMIT-B Study Section in June 2011 and awarded a priority score of 12 (2nd percentile) with no recommended budget cuts. Our overall aims are to continue the development, evaluation and validation of a novel magnetic resonance imaging (MRI) technique that is a sensitive indicator of tumor status, before and after treatment, and which provides unique information non-invasively on tissue microstructure. Grant CA109106 was subsequently awarded with a 62% budget reduction compared to what the Study Section recommended. The work being performed with that grant has therefore been amended and substantially reduced in scope, and it no longer will support most of the animal studies or comparisons of treatment effects that were proposed and approved. This proposal aims to secure supplementary support for those studies that were approved but not funded, and which we (and the Study Section) consider essential as part of our evaluation of this new methodology. Previous studies have convincingly shown that diffusion weighted MRI (DW-MRI) can report on changes in tumors during growth and following treatment. However, detectable changes occur only after a critical time has elapsed, when cell density has altered sufficiently, and conventional DW-MRI is not sensitive to earlier or more subtle changes within cells. We have developed an alternative technique, oscillating gradient spin-echo (OGSE) DW-MRI, which is uniquely sensitive to microstructural features much smaller than a cell which restrict the free diffusion of tissue water. OGSE measurements may be sensitized selectively to features of different sizes, they appear to be able to detect changes within cells before there are changes in cell density, and they provide a new type of spectral data which can be analyzed to obtain quantitative structural information. We have shown that OGSE imaging reveals greater heterogeneity within tumors, and at higher contrast, that it is sensitive to intra-cellular features such as nuclear size, and that it seems more sensitive to earlier changes in tumors following treatment. We propose to apply optimized OGSE methods to measure changes that occur with the growth of tumors, and in response to three different classes of targeted treatments, in mouse models in vivo. We will establish how early OGSE methods can detect the response of tumors to treatments, how well these changes predict later outcomes, and which OGSE parameters correlate with changes in cellularity, apoptosis and proliferation. The OGSE data will be correlated with co-registered quantitative histological and immunohistochemical sections of the same tumor to verify the interpretation of the measurements. We will also further assist the interpretation of OGSE data by performing elaborate computer simulations of water in compartmental systems of appropriate complexity. Our overall aim is to validate OGSE methods as an experimental tool for pre-clinical studies of tumors.

Public Health Relevance

Reliable and sensitive methods for assessing the response of tumors to treatments are critical for the successful management of cancer and as investigational tools in pre-clinical research, but at present our ability to detect early response and predict the outcome of targeted treatments is poor. Repeatable, quantitative, non-invasive imaging methods which can reliably assess tumor response would aid the development of new treatments. The research proposed would provide a new MRI technique for non- invasive imaging of tumors which can be used to detect and assess their response to treatment sooner and more accurately than current methods, and which promises to become a useful tool in preclinical research and provide insights into how better to use and interpret current imaging methods.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Zhang, Huiming
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Vanderbilt University Medical Center
Schools of Medicine
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Jiang, Xiaoyu; Li, Hua; Xie, Jingping et al. (2016) In vivo imaging of cancer cell size and cellularity using temporal diffusion spectroscopy. Magn Reson Med :
Li, Hua; Jiang, Xiaoyu; Xie, Jingping et al. (2016) Impact of transcytolemmal water exchange on estimates of tissue microstructural properties derived from diffusion MRI. Magn Reson Med :
Xu, Junzhong; Li, Ke; Smith, R Adam et al. (2016) A comparative assessment of preclinical chemotherapeutic response of tumors using quantitative non-Gaussian diffusion MRI. Magn Reson Imaging 37:195-202
Xu, Junzhong; Li, Hua; Li, Ke et al. (2016) Fast and simplified mapping of mean axon diameter using temporal diffusion spectroscopy. NMR Biomed 29:400-10
Jiang, Xiaoyu; Li, Hua; Zhao, Ping et al. (2016) Early Detection of Treatment-Induced Mitotic Arrest Using Temporal Diffusion Magnetic Resonance Spectroscopy. Neoplasia 18:387-97
Jiang, Xiaoyu; Li, Hua; Xie, Jingping et al. (2016) Quantification of cell size using temporal diffusion spectroscopy. Magn Reson Med 75:1076-85
Li, Hua; Jiang, Xiaoyu; Xie, Jingping et al. (2016) Time-Dependent Influence of Cell Membrane Permeability on MR Diffusion Measurements. Magn Reson Med 75:1927-34
Tian, Xin; Li, Hua; Jiang, Xiaoyu et al. (2016) Evaluation and comparison of diffusion MR methods for measuring apparent transcytolemmal water exchange rate constant. J Magn Reson 275:29-37
Li, Ke; Li, Hua; Zhang, Xiao-Yong et al. (2016) Influence of water compartmentation and heterogeneous relaxation on quantitative magnetization transfer imaging in rodent brain tumors. Magn Reson Med 76:635-44
Li, Hua; Zu, Zhongliang; Zaiss, Moritz et al. (2015) Imaging of amide proton transfer and nuclear Overhauser enhancement in ischemic stroke with corrections for competing effects. NMR Biomed 28:200-9

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