Imaging tumor metabolism with hyperpolarized 13C-labeled cell substrates

Abstract:

Abstract Molecular imaging can play an important role in predicting and detecting tumor responses to treatment and thus in guiding treatment in individual patients [1]. Nuclear spin hyperpolarization can increase sensitivity in the magnetic resonance experiment by >10,000x. This has allowed imaging of injected hyperpolarized 13C labelled cell substrates in vivo and, more importantly, their metabolic conversion into other metabolites. We have been using this metabolic imaging technique both to detect treatment response and to investigate the tumor microenvironment. A recent perspective on this field of research is given in [2]. Exchange of hyperpolarized 13C label between lactate and pyruvate and net flux of label between glucose and lactate have been shown to decrease post-treatment and hyperpolarized [1,4-13C]fumarate has been shown to detect subsequent cell necrosis. Tumor pH can be imaged using hyperpolarized H13CO3- and redox state can be determined by monitoring the oxidation and reduction of [1-13C]ascorbate and [1-13C]dehydroascorbate respectively. In this talk I will discuss more recent work in which we have used hyperpolarized [1-13C]pyruvate to investigate metabolism in PDX models of glioblastoma. These measurements have shown significant heterogeneity between tumors derived from different patients, which we believe is related to underlying oncogenic mutations. I will also show how hyperpolarized [1-13C]pyruvate can be used to follow the progression of pancreatic precursor lesions, in a genetically engineered mouse model of the disease, which potentially could be used clinically to guide earlier intervention [3]. Finally I will discuss how we have used hyperpolarized [U-2H, U-13C]glucose [4] to investigate flux in the pentose phosphate pathway (PPP) and the relationship between PPP flux and the rate of reduction of hyperpolarized [1-13C]dehydroascorbate. Metabolic imaging with hyperpolarized 13C-labelled cell substrates has recently translated to the clinic with a study in prostate cancer [5] and we have conducted our first clinical study in Cambridge using this technique earlier this year. 1. Brindle, K. Nature Rev Cancer 8, 94-107 (2008). 2. Brindle, K.M. J. Amer. Chem. Soc. 137, 6418-6427 (2015). 3. Serrao, E.M., et al. Gut 65, 465-475 (2016). 4. Rodrigues, T.B., et al. Nat Med 20, 93-97 (2014). 5. Nelson, S.J., et al. Science Translational Medicine 5, 198ra108 (2013). Citation Format: Kevin M. Brindle. Imaging tumor metabolism with hyperpolarized 13C-labeled cell substrates. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr IA14.

Authors:

KM Brindle

Journal:

Cancer Research

Citation info:

77(2_Supplement):ia14-ia14

Publication date:

15th Jan 2017

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