This project consists of both (1) the technical development of novel bioengineering methods for non-invasive imaging of metabolite transport and metabolism and (2) the application of these methods to study cancer biology. The non-invasive imaging is based on the emerging field of hyperpolarized MRI, which is providing valuable new metabolic information for cancer imaging applications. Using this technique, we are able to greatly increase the MR signal of injected substrates, facilitating the ability to acqure fast metabolic data in seconds. The translation potential of this technique has been demonstrated by the first clinical trial in prostate cancer patients with hyperpolarized pyruvate recently completed by our group. Unlike previous hyperpolarized imaging methods, which only probe metabolic conversions, the proposed projects use diffusion-weighted imaging in order to additionally characterize transport of pyruvate and its metabolic product, lactate. This is of grea biomedical importance since the transport of lactate out of cells has promise for predicting aggressiveness of cancer, progression to metastatic disease and response to therapy, as this creates an acidic environment. There are currently no non-invasive imaging methods to measure metabolite transport in vivo. The developments in this proposal are designed specifically to provide and test such methods. This proposal includes cell studies to measure the mechanisms of cellular transport-mediated contrast, preclinical studies to evaluate diffusivity as a biomarker for transport and metabolism in vivo, and development of a novel hyperpolarized diffusion-weighted imaging method that can be translated into the clinical setting for improved characterization of tumor aggressiveness. Both the cell and preclinical studies also require development of specialized hyperpolarized 13C diffusion-weighted methods because, unlike conventional MRI, the signal decay is rapid and unrecoverable. These studies will use cancer cells and cancer models to evaluate tumor characterization capabilities, and the results will be used to design an optimized clinical protocol, which will be validated through preclinical studies. The proposed novel techniques have the potential to transform tumor characterization through improved prediction of aggressiveness and progression to metastatic disease.

Public Health Relevance

This project will develop and test new metabolite diffusion MRI methods to non-invasively measure metabolism and cellular transport. Both of these mechanisms are highly implicated in aggressive types of cancer, as well as other diseases such as kidney failure and non-alcoholic fatty liver disease. This method has significant potential to improve healthcare by better characterizing disease severity and improving outcome predictions following treatment.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Liu, Guoying
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Jiang, Wenwen; Larson, Peder E Z; Lustig, Michael (2018) Simultaneous auto-calibration and gradient delays estimation (SAGE) in non-Cartesian parallel MRI using low-rank constraints. Magn Reson Med 80:2006-2016
Wei, Hongjiang; Cao, Peng; Bischof, Antje et al. (2018) MRI gradient-echo phase contrast of the brain at ultra-short TE with off-resonance saturation. Neuroimage 175:1-11
Zhu, Xucheng; Gordon, Jeremy W; Bok, Robert A et al. (2018) Dynamic diffusion-weighted hyperpolarized 13 C imaging based on a slice-selective double spin echo sequence for measurements of cellular transport. Magn Reson Med :
Larson, Peder E Z; Chen, Hsin-Yu; Gordon, Jeremy W et al. (2018) Investigation of analysis methods for hyperpolarized 13C-pyruvate metabolic MRI in prostate cancer patients. NMR Biomed 31:e3997
Gordon, Jeremy W; Hansen, Rie B; Shin, Peter J et al. (2018) 3D hyperpolarized C-13 EPI with calibrationless parallel imaging. J Magn Reson 289:92-99
Maidens, John; Gordon, Jeremy W; Chen, Hsin-Yu et al. (2018) Spatio-Temporally Constrained Reconstruction for Hyperpolarized Carbon-13 MRI Using Kinetic Models. IEEE Trans Med Imaging 37:2603-2612
Marco-Rius, Irene; Gordon, Jeremy W; Mattis, Aras N et al. (2018) Diffusion-weighted imaging of hyperpolarized [13 C]urea in mouse liver. J Magn Reson Imaging 47:141-151
Gordon, Jeremy W; Milshteyn, Eugene; Marco-Rius, Irene et al. (2017) Mis-estimation and bias of hyperpolarized apparent diffusion coefficient measurements due to slice profile effects. Magn Reson Med 78:1087-1092
Gordon, Jeremy W; Vigneron, Daniel B; Larson, Peder E Z (2017) Development of a symmetric echo planar imaging framework for clinical translation of rapid dynamic hyperpolarized 13 C imaging. Magn Reson Med 77:826-832
Ohliger, Michael A; von Morze, Cornelius; Marco-Rius, Irene et al. (2017) Combining hyperpolarized 13 C MRI with a liver-specific gadolinium contrast agent for selective assessment of hepatocyte metabolism. Magn Reson Med 77:2356-2363

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