title: Model free approach to kinetic analysis of real-time hyperpolarized 13C magnetic resonance spectroscopy data.
abstract: Real-time detection of the rates of metabolic flux, or exchange rates of endogenous enzymatic reactions, is now feasible in biological systems using Dynamic Nuclear Polarization Magnetic Resonance. Derivation of reaction rate kinetics from this technique typically requires multi-compartmental modeling of dynamic data, and results are therefore model-dependent and prone to misinterpretation. We present a model-free formulism based on the ratio of total areas under the curve (AUC) of the injected and product metabolite, for example pyruvate and lactate. A theoretical framework to support this novel analysis approach is described, and demonstrates that the AUC ratio is proportional to the forward rate constant k. We show that the model-free approach strongly correlates with k for whole cell in vitro experiments across a range of cancer cell lines, and detects response in cells treated with the pan-class I PI3K inhibitor GDC-0941 with comparable or greater sensitivity. The same result is seen in vivo with tumor xenograft-bearing mice, in control tumors and following drug treatment with dichloroacetate. An important finding is that the area under the curve is independent of both the input function and of any other metabolic pathways arising from the injected metabolite. This model-free approach provides a robust and clinically relevant alternative to kinetic model-based rate measurements in the clinical translation of hyperpolarized (13)C metabolic imaging in humans, where measurement of the input function can be problematic.
authors.affiliation: Cancer Research UK (CR-UK) and Engineering and Physical Sciences Research Council (EPSRC) Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Hill
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Orton
authors.forename: Erika
authors.initials: E
authors.lastname: Mariotti
authors.forename: Jessica K R
authors.initials: JK
authors.lastname: Boult
authors.forename: Rafal
authors.initials: R
authors.lastname: Panek
authors.forename: Maysam
authors.initials: M
authors.lastname: Jafar
authors.forename: Harold G
authors.initials: HG
authors.lastname: Parkes
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.forename: Maria Falck
authors.initials: MF
authors.lastname: Miniotis
authors.forename: Nada M S
authors.initials: NM
authors.lastname: Al-Saffar
authors.forename: Mounia
authors.initials: M
authors.lastname: Beloueche-Babari
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Eykyn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007191:Indazoles; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008962:Models, Theoretical; D011773:Pyruvates / Q000737:chemistry; D013449:Sulfonamides; D023041:Xenograft Model Antitumor Assays
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D007191:Indazoles; D011773:Pyruvates; D013449:Sulfonamides; D019344:Lactic Acid
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