Sunday, May 5, 2024
5/5/2024
Project Summary. Aberrant glycolysis and mitochondrial function are features of most liver diseases including hepatocellular carcinoma (HCC). Despite these metabolic signatures, the absence of methods to noninvasively assess metabolic fluxes in vivo limits the accurate characterization of liver diseases and in turn impedes the development of new therapies. In the proposed study, we will employ novel hyperpolarized (HP) 13C probes to image glycolysis, a pathway that plays a critical role in HCC onset and progression. Importantly, our cross-disciplinary research team has made significant advancements in the design and application of HP 13C-glycerate probes. We have demonstrated that HP [1-13C]glycerate is a non-toxic substrate with a long T1 relaxation time (60 sec), and this HP probe is sensitive to alterations in liver metabolism in vivo, offering inroads for clinical translation. In addition, our recent studies in HCC (diethylnitrosamine [DEN]-induced rat model) demonstrated that HP [1- 13C]glycerate can successfully distinguish HCC from healthy liver based upon the unique metabolic fluxes detected in the cancerous tissue. Given these advancements, we now propose that the HP 13C-glycerate scaffold can be systematically optimized to yield 2nd generation HP probes, which provide highly sensitive analyses of enzymatic reactions in the liver and diagnostic assessments of abnormal fluxes in HCC. The overarching goal of the proposed project is to use the HP 13C-glycerate technology to establish in vivo imaging biomarkers for assessing altered metabolism during HCC development. To this end, in Aim 1, we will synthesize a focused library of 2nd generation 13C-glycerate probes that are specifically designed to increase the metabolic information obtained from HP experiments. In Aim 2, we will analyze the physicochemical properties of these probes in order to determine top agents to advance towards in vivo HP studies. In Aim 3, we will initially establish imaging biomarkers for HP 13C-glycerates in the DEN rat model and identify specific probes that provide clear metrics for distinguishing HCC. These 13C-glycerate probes will then be used to evaluate a stepwise progression from normal liver to HCC in the DEN model. Four pathological states will be examined: baseline, chronic inflammation, fibrosis, and HCC. In vivo metrics for glycolysis will be compared among the states, and these results will be validated with tissue analyses. Overall, the proposed studies offer an innovative strategy for tackling a challenge of clinical significance. State-of-the-art HP probes will be used to assess altered glycolysis in hepatocarcinogenesis. This technology will in turn provide specific in vivo biomarkers that represent the metabolic pathways of interest in HCC, providing a noninvasive method for assessing disease progression in at- risk patients.
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