The overall goals of this proposal are to develop and validate a novel magnetic resonance imaging method for mapping tissue protein and creatine content in order to detect and characterize tumor cellular and metabolic features. The ability to assess such tumor attributes will have a broad range of both clinical and preclinical applications, particularly since such fundamental biophysical characteristics are highly dissimilar to that found in the surrounding normal tissue and could serve as improved early indicators of treatment response as compared to conventional assays of gross tumor volume, which often change much later in the course of therapy. The proposed methods for achieving this objective include a significant and novel reformulation of chemical exchange saturation transfer (CEST) imaging. There are inherent and critical technical obstacles to the widespread application of CEST methods and major limitations on their use in practice. CEST suffers from a lack of quantification and is highly susceptible to artifacts originating from static field inhomogeneities lipid content, spectral overlap of multiple metabolites signals, and the inherently asymmetric background macromolecular resonance. Chemical exchange rotation transfer (CERT) is our proposed reformulation of CEST that overcomes the shortcomings of CEST. Furthermore, CERT can act as an exchange rate filter and can separate the contribution of creatine from that of other overlapping metabolites. We will 1) develop, optimize, and validate CERT imaging methods; 2) quantify tissue changes in protein and creatine content in rat models of tumor growth and remission; and 3) quantify tissue changes in protein and creatine content in cancer patients treated with Bevacizumab, which restores the blood brain barrier and eliminates inflammation, and hence makes conventional post-contrast T1 and diffusion imaging uninformative.

Public Health Relevance

The overall goals of this proposal are to develop and validate a novel magnetic resonance imaging method for mapping tissue protein and creatine content in order to detect and characterize tumor cellular and metabolic features. These methods will provide the cancer community with imaging approaches that characterize the underlying biology of tumors and address questions of treatment response and that can be incorporated into both clinical trials and standard-of-care practice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184693-05
Application #
9318135
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Menkens, Anne E
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Dortch, Richard D; Bagnato, Francesca; Gochberg, Daniel F et al. (2018) Optimization of selective inversion recovery magnetization transfer imaging for macromolecular content mapping in the human brain. Magn Reson Med 80:1824-1835
Gochberg, Daniel F; Does, Mark D; Zu, Zhongliang et al. (2018) Towards an analytic solution for pulsed CEST. NMR Biomed 31:e3903
Lin, Eugene C; Li, Hua; Zu, Zhongliang et al. (2018) Chemical exchange rotation transfer (CERT) on human brain at 3 Tesla. Magn Reson Med 80:2609-2617
Zhang, Xiao-Yong; Wang, Feng; Xu, Junzhong et al. (2018) Increased CEST specificity for amide and fast-exchanging amine protons using exchange-dependent relaxation rate. NMR Biomed 31:
Zu, Zhongliang; Li, Hua; Xu, Junzhong et al. (2017) Measurement of APT using a combined CERT-AREX approach with varying duty cycles. Magn Reson Imaging 42:22-31
Zhang, Xiao-Yong; Xie, Jingping; Wang, Feng et al. (2017) Assignment of the molecular origins of CEST signals at 2?ppm in rat brain. Magn Reson Med 78:881-887
Zhang, Xiao-Yong; Wang, Feng; Li, Hua et al. (2017) Accuracy in the quantification of chemical exchange saturation transfer (CEST) and relayed nuclear Overhauser enhancement (rNOE) saturation transfer effects. NMR Biomed 30:
Zu, Zhongliang; Louie, Elizabeth A; Lin, Eugene C et al. (2017) Chemical exchange rotation transfer imaging of intermediate-exchanging amines at 2 ppm. NMR Biomed 30:
Zhang, Xiao-Yong; Wang, Feng; Jin, Tao et al. (2017) MR imaging of a novel NOE-mediated magnetization transfer with water in rat brain at 9.4?T. Magn Reson Med 78:588-597
Gore, John C; Zu, Zhongliang; Wang, Ping et al. (2017) ""Molecular"" MR imaging at high fields. Magn Reson Imaging 38:95-100

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