Académie royale de Médecine de Belgique


Résumé de Kevin M. Brindle

(Séance du 15 décembre 2012)


par K.M. BRINDLE (Department of Biochemistry, University of Cambridge), invité.  

Patients with similar tumour types can have 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 [1].

We have been developing methods for detecting the early responses of tumours to therapy, including magnetic resonance (MR) imaging of tumour cell metabolism using hyperpolarized 13C-labelled cellular metabolites.  Nuclear spin hyperpolarization can increase sensitivity in the MR experiment by >10,000x.  This has allowed us to image the location of labelled cell substrates and, more importantly, their metabolic conversion into other metabolites.  These substrates include pyruvate [2], lactate [3], glutamine [4], glutamate [5], fumarate [6], bicarbonate [7] and ascorbate [8]We have shown that exchange of hyperpolarized 13C label between lactate and pyruvate can be imaged in animal models of lymphoma and glioma and that this flux is decreased post-treatment [2,9]We showed that hyperpolarized [1,4-13C]fumarate can be used to detect tumour cell necrosis post treatment in lymphoma [6] and that both the polarized pyruvate and fumarate experiments can detect early evidence of treatment response in a breast tumour model [10] and also early responses to anti-vascular [11] and anti-angiogenic drugs [12]Fumarate can also be used to detect necrosis in other tissues, such as the kidney [13]We have shown that tissue pH can be imaged from the ratio of the signal intensities of hyperpolarized H13CO3- and 13CO2 following intravenous injection of hyperpolarized H13CO3¯ [7] and that tumour redox state can be determined by monitoring the oxidation and reduction of [1-13C]ascorbate and [1-13C]dehydroascorbate respectively [8]More recently we have shown that we can monitor tumour glycolysis by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate.  Labelled lactate production was higher in the tumour than in surrounding normal tissue and was markedly decreased at 24 h after treatment with a chemotherapeutic drug.

We have recently obtained funding for clinical trials with polarised pyruvate and fumarate to detect treatment response in lymphoma, glioma and breast cancer patients.

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2.      Day S.E. et al., Nat. Med. 13, 1382-1387 (2007).

3.      Kennedy, B.W.C., et al. J. Am. Chem. Soc. 134, 4969−4977 (2012).

4.      Gallagher F. et al. Magn. Reson. Med. 60, 253-257 (2008).

5.      Gallagher F. et al.Magn. Reson. Med. 66, 18-23 (2011).

6.      Gallagher F.A. et al., Proc. Natl. Acad. Sci. USA 106, 19801-19806 (2009).

7.      Gallagher F. et al., Nature 453, 940-943 (2008).

8.      Bohndiek S.E. et al., J. Am. Chem. Soc. 133, 11795-11801 (2011).

9.      Day S.E. et al., Magn. Reson. Med. 65, 557-563 (2011).

10.    Witney T.H. et al., Brit. J. Cancer 103, 1400-1406 (2010).

11.    Bohndiek, S.E., et al. Mol Cancer Ther 9, 3278-3288 (2010).

12.    Bohndiek, S.E., et al. Cancer Research 72, 854-864 (2012).

13.    Clatworthy, M.R., et al. Proc. Natl. Acad. Sci. USA. 109, 13374-13379 (2012).