The primary aim of my laboratory is to develop clinically applicable imaging methods that can be used to detect early tumour responses to treatment. These could be used in early stage clinical trials of new drugs to get an indication of efficacy and subsequently, in the clinic, to guide therapy in individual patients.
Patients with similar tumour types can show markedly different responses to the same therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment for a specific patient (Brindle, Nat. Rev. Cancer 2008; 8: 1).
Through a partnership with GE Healthcare we are developing nuclear spin hyperpolarization as a novel tool for molecular imaging. Nuclear spin polarization offers enormous gains in sensitivity, as much as 10,000x, which makes it possible not only to image the distribution of isotopically-labelled cellular metabolites, but also their enzymatic transformation into other species. This provides us with potentially more sensitive ways to detect tumour responses to treatment and, with some substrates, is providing new insights into cellular metabolism in vivo. For example, using the reduced and oxidised forms of vitamin C (ascorbic acid), which have been labelled with hyperpolarised 13C, we are able to image tumour redox state in vivo.
Aberrant glycosylation is a hallmark of cancer. We are developing a novel molecular imaging platform for the non-invasive assessment of tumour glycosylation, in which sugar analogues are incorporated metabolically by tumour cells in vivo and subsequently detected by a highly selective chemical reaction (“click chemistry”) with a reporter probe that has been labelled with an imaging agent. This methodology could provide new insights into tumour cell proliferation, response to therapy, and metastasis.
1. Day, S. E., Kettunen, M. I., Gallagher, F. A., Hu, D.-E., Lerche, M., Wolber, J., Golman, K., Ardenkjaer-Larsen, J. H., and Brindle, K. M. Detecting tumour response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy, Nature Medicine 13: 1382 – 1387, 2007.
2. Gallagher, F. A., Kettunen, M. I., Day, S. E., Hu, D.-E., Ardenkjær-Larsen, J. H., in ‘t Zandt, R., Jensen, P. R., Karlsson, M., Golman, K., Lerche, M. H., and Brindle, K. M. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labeled bicarbonate, Nature 453: 940-943, 2008.
3. Bohndiek, S. E., Kettunen, M. I., Hu, D., Kennedy, B. W. C., Boren, J., Gallagher, F. A., Brindle, K. M. Hyperpolarized 1-13C-ascorbic and dehydroascorbic acid: Vitamin C as a probe for imaging redox status in vivo. J. Amer. Chem. Soc. 133: 11795-11801, 2011.
4. Rodrigues, T. B., Serrao, E. M., Kennedy, B. W. C., Hu, D., Kettunen, M. I. and Brindle, K. M. Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C labeled glucose. Nature Med 20: 93-97, 2014.
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