Abstract SY18-02: Hyperpolarized MRI: An emerging technology for metabolic imaging of cancer
Authors: Brindle Kevin M. 
Published: June 2012

Abstract
Magnetic resonance imaging (MRI) gives excellent images of soft tissues, such as tumors. The technique works by mapping, in 3-D, the distribution and MR properties of tissue water protons, which are very abundant (60-70 M in tissues). We can also use magnetic resonance spectroscopy (MRS) to detect metabolites in vivo. The problem is that these molecules are present at 10,000x lower concentration than the protons in tissue water. This makes them hard to detect and almost impossible to image, except at very low resolution. In collaboration with GE Healthcare we have been developing a technique, termed “hyperpolarization,” that increases sensitivity in the MR experiment by more than 10,000x [1]. With this technique we inject a hyperpolarized 13C-labeled molecule and now have sufficient sensitivity to image the distribution of this molecule in the body and, more importantly, the distribution of the metabolites produced from it. The principle limitation of the method is the relatively short lifetime of the polarization, which for those molecules that have been used in vivo is between 10 and 30 sec. Although methods have been proposed to extend the lifetime of the polarization these have yet to find a practical application in vivo. This means that currently injection and imaging must be accomplished within 2-3 minutes, which limits detection of metabolism to those molecules that are very rapidly taken up by cells and metabolized. Nevertheless, despite this limitation, the technique has the potential to provide new insights into tumor metabolism in vivo and to translate to the clinic, where it could be used to detect disease, give prognostic information and to detect treatment response. It is in this latter area that my laboratory has focused and which is the subject of this talk.
Conventionally, treatment response in the clinic has been assessed using imaging measurements of reductions in tumor size. The problem with this approach is that it may take weeks or even months for this to become apparent and in some cases, for example with antivascular or cytostatic drugs, there may be no decrease in tumor size at all, despite a positive response to treatment. Imaging of tumor metabolism, or some other aspect of tumor biology, can give much earlier evidence of treatment response [2]. Currently the most widely used technique in the clinic for metabolic imaging of early treatment response is FDG-PET, in which positron emission tomography is used to measure tumor uptake of the 18F-labelled glucose analog, 2-fluoro-2-deoxy-D-glucose. While a powerful technique, it does not work for all tumors, such as prostate tumors, which show relatively low glucose uptake, and tumors in the brain, where tumor uptake can be masked by high uptake in normal surrounding brain tissue. Furthermore, radiation dose may make this technique problematic if used to guide therapy in an “image – treat – image” paradigm, especially in relatively young patients, such as breast cancer patients. We have been developing metabolic imaging methods, based on hyperpolarized cell substrates, which can be used to detect treatment response and which have the potential to translate to the clinic. These substrates include pyruvate [3], glutamine [4], fumarate [5], and bicarbonate [6] (reviewed in [7]).
In a murine lymphoma, we showed that flux of hyperpolarized 13C label between pyruvate and lactate, in the reaction catalyzed by lactate dehydrogenase (LDH), could be imaged and that this flux was decreased in treated tumors undergoing drug-induced cell death [3]. Flux was decreased due to a reduction in tumor cellularity and a loss of enzyme and coenzyme (NAD(H)) from the cell. The latter was shown to be due to DNA-damage-dependent activation of polyADP-ribose polymerase (PARP), for which NAD+ is a substrate. We suggested that the technique could be used for response monitoring in the clinic, in the same way as FDG has been used with PET, and demonstrated that the techniques had similar sensitivities for detecting response in this murine lymphoma model [8]. While both FDG PET and the hyperpolarized pyruvate experiment detect tumor damage following treatment they do not necessarily detect tumor cell death. More recently, using another substrate, hyperpolarized [1,4-13C2]fumarate, we have demonstrated that we can detect cell death directly, in the form of cellular necrosis [5]. More recently we have shown that the technique will work with other tumor types, breast [9] and glioma [10], and with other types of drugs, notably combretastatin A4 phosphate, which is an antivascular drug that in the short term has no effect on tumor size [11]. In the latter case we showed that measurements of hyperpolarized pyruvate and fumarate metabolism could provide a more sustained and sensitive indicator of response to this vascular disrupting agent than dynamic contrast agent-enhanced (DCE) or diffusion-weighted (DW) MRI respectively, which have been used in the clinic to detect the action of antivascular and antiangiogenic drugs.
Since a clinical trial with polarized [1-13C]pyruvate is due to start soon in prostate cancer at UCSF there is good reason to believe that the techniques described here could translate to the clinic in the near future.
References
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2. Brindle, K. Nature Rev. Cancer 8, 1-14 (2008).
3. Day, S.E., et al. Nature Med 13, 1382-1387 (2007).
4. Gallagher, F.A., et al. Magn Reson Med 60, 253-257 (2008).
5. Gallagher, F.A., et al. Proceedings of the National Academy of Sciences of the United States of America 106, 19801-19806 (2009).
6. Gallagher, F.A., et al. Nature 453, 940-943 (2008).
7. Gallagher, F., et al. Prog. NMR Spectrosc. 55, 285-295 (2009).
8. Witney, T., et al. Neoplasia 6, 574-582 (2009).
9. Witney, T.H., et al. Brit. J. Cancer In press (2010).
10. Day, S.E., et al. Magn Reson Med In press (2010).
11. Bohndiek, S.E., et al. Molec. Cancer Ther. In press (2010).
Acknowledgements: This work was funded with grants from Cancer Research UK and the Leukemia and Lymphoma Society. I also acknowledge research support from GE Healthcare.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY18-02. doi:10.1158/1538-7445.AM2011-SY18-02