Imaging Response to Treatment and the Tumor Microenvironment with Hyperpolarized 13C-Labeled Cell Substrates

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Kevin M. Brindle is Professor of Biomedical Magnetic Resonance in the Department of Biochemistry at the University of Cambridge and a senior group leader in the Cancer Research UK Cambridge Research Institute. He became involved in magnetic resonance in 1978 when he started a D. Phil. on 1H NMR studies of cells with the late Prof. Iain Campbell FRS at the University of Oxford, where he was also an undergraduate. He joined the laboratory of Prof Sir George Radda FRS at Oxford in 1983 and in 1986 became a Royal Society University Research Fellow. In 1990 he moved to a lectureship at the University of Manchester and in 1993 to a lectureship in Cambridge, where he became Professor in 2005. His initial work involved studies of the kinetic properties of enzymes in cells and tissues using molecular genetic, isotope exchange and magnetization transfer methods. This also involved the development of NMR methods to study proteins in intact cells. In 1990 he started work in the field of cancer, initially using DCE MRI to study the action of anti-vascular drugs and subsequently he developed methods to detect tumor cell death post-treatment, which included a targeted MRI contrast agent. Since 2006 he has been working on metabolic imaging with hyperpolarized 13C-labelled cell substrates to detect treatment response in tumors. Prof. Brindle is currently associated with the editorial boards of NMR in Biomedicine, Contrast Media and Molecular Imaging and Magnetic Resonance Materials in Physics, Biology and Medicine and is a senior editor at a new on-line journal entitled Cancer and Metabolism. He sits on Cancer Research UK’s Science Committee and its Biomarker Expert Review Panel. He was elected a Fellow of the Academy of Medical Sciences in 2012 and was awarded the European Society of Molecular Imaging Award in 2013 and the Gold Medal of the World Molecular Imaging Society in 2014.

A better understanding of tumor biology has led to the development of targeted therapies, in which a drug is designed to disrupt a specific biochemical pathway important for tumor cell survival or proliferation. The introduction of these drugs into the clinic has shown that patients can vary widely in their responses. Molecular imaging is likely to play an increasingly important role in predicting and detecting these responses and thus in guiding treatment in individual patients. We have been developing methods for detecting the early responses of tumors to therapy, including metabolic imaging with hyperpolarized 13C-labelled substrates, which we have used both to detect treatment response and to investigate the tumor microenvironment. 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. More recently we have shown that we can follow, using hyperpolarized [1-13C]pyruvate, 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.

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