Assessment of tumor metabolism using hyperpolarized 13C magnetic resonance spectroscopy [electronic resource]

Unlike normal tissues, solid tumors have a metabolic phenotype that favors energy-inefficient glycolysis rather than more efficient, but oxygen consuming, oxidative phosphorylation, even when oxygen levels are adequate. This metabolic shift towards glycolysis, discovered by Warburg in 1924, has been studied for more than 80 years, but the mechanism of the phenomena is still unclear due to lack of tools for in vivo investigation. Dynamic nuclear polarization in combination with the recent development of a dissolution process that retains the increased polarization into the liquid state opened new possibilities for the real-time investigation of in vivo metabolism using C13 magnetic resonance spectroscopy. In particular, hyperpolarized [1-13C]pyruvate, a substrate occupying a key nodal point in the glucose metabolic pathway, has been successfully demonstrated as a neoplasm biomarker via elevated lactate labeling in tumors. However, additional downstream products of pyruvate metabolism, such as that occur in mitochondria of brain tumor, have been veiled due to low signal-to-noise ratios. The first part of the thesis is on the quantitative assessment of mitochondrial function in normal rat brain and glioma by detecting 13C-bicarbonate following the bolus injection of [1-13C]pyruvate. The feasibility of quantitatively detecting 13C-bicarbonate in tumor-bearing rat brain is demonstrated for the first time. The optimized protocol for chemical shift imaging and high concentration of hyperpolarized [1-13C]pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Moreover, the immediate response to dichloroacetate treatment, which upregulates pyruvate flux to acetyl-CoA, is also presented. It is demonstrated that the simultaneous detection of lactate and bicarbonate provides a tool for a more comprehensive analysis of glioma metabolism and the assessment of metabolic agents as anti-cancer drugs. In the second part of the thesis, further investigation on mitochondrial metabolism, including tricarboxylic acid cycle, is presented by acquiring single-time point chemical shift imaging data from rat brain in vivo after administration of highly concentrated [2-13C]pyruvate. A C13 surface coil optimized for rat brain was built to increase sensitivity of signal detection. [5-13C]glutamate, [1-13C]acetyl carnitine, and [1-13C]citrate were detected besides [2-13C]pyruvate and [2-13C]lactate, for the first time in brain. Change of the tricarboxylic acid cycle activity in brain was also investigated by infusing dichloroacetate. The increase of [5-13C]glutamate was detected primarily from brain, whereas [1-13C]acetyl carnitine was increased in peripheral tissues after the infusion of dichloroacetate. The third part focuses on dynamic measurements of hyperpolarized substrates to obtain exchange rates in addition to concentrations, and proposes the apparent conversion rate as a new metric to detect glioma by comparing the conversion rates in glioma, normal appearing brain, and basilar vasculature in female Sprague-Dawley rats with C6 glioma cells implanted. Whereas single-time point measurements give a snapshot image of tissue metabolism, the estimated apparent rate constant yielded a better differentiation between the tissue types than the lactate-to-pyruvate ratio, which has been the most common metric used to date. This study demonstrates the feasibility of quantitatively detecting C13-labeled bicarbonate and glutamate in vivo, permitting the assessment of dichloroacetate-modulate changes in pyruvate dehydrogenase flux in both normal rat brain and glioma. The simultaneous detection of both lactate dehydrogenase and pyruvate dehydrogenase activities will likely improve our ability to both assess and monitor metabolic therapies of brain and other cancers by providing non-invasive in vivo measures of glycolysis and oxidative phosphorylation.

Keywords: Electrical Engineering
Advisor: Spielman Daniel (Daniel Mark)
Moseley Michael E. (Michael Eugene)
Nishimura Dwight George advisor. Thesis advisor