Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY (30-line limit) Pyruvate is a metabolite that sits at the intersection of key metabolic pathways; it is the end product of glycolysis, the starting point for gluconeogenesis, and ultimately it is destined for transport into mitochondria as a master fuel that drives ATP production by oxidative phosphorylation. Altered pyruvate metabolism plays an especially prominent role in biology of metabolically challenged diseases such as cancer. Metabolic alterations in cancer are numerous, including aerobic glycolysis, reduced oxidative phosphorylation and the increased gen- eration of biosynthetic intermediates needed for cell growth and proliferation. MRI is based on the detection of nuclear spin magnetization, which is a product of spin density and the degree of spin alignment (i.e., polarization). Conventional MRI detects signals arising from the very small “thermal" proton spin polarization, typically of order 10–5 at clinical scanner field strengths (1.5 – 7T). This low spin polarization limits the sensitivity of MRI to detect molecules at low concentration. Hyperpolarization techniques can be used to increase nuclear spin polarization by several orders of magnitude – up to the order of unity – with corresponding gains in the detection sensitivity threshold. Recent advances in hyperpolarized (HP) MRI, pioneered by our team and others, allow in vivo tracking of metabolic transformations of injected HP 13C-pyruvate to multiple downstream metabolites, resulting in multi- ple new imaging biomarkers that can flag altered metabolism in diseases such as cancer and heart disease, inform disease progression, and guide treatment decisions. For example, HP 13C-pyruvate MRI has shown met- abolic reprogramming in response to cancer treatment within only a few days in glioma, glioblastoma multiforme, gastric cancer, and breast cancer animal studies. While HP 13C-pyruvate MRI has become a highly acclaimed way to assess pyruvate metabolism in vivo and rival the efficacy of Positron Emission Tomography, only a hand- ful research sites have been conducting early-phase clinical trials of HP 13C-pyruvate MRI since its first-in-human debut in 2010. Major hurdles include the need for a hyperpolarizer, a HP 13C-pyruvate production workflow, and the need for MRI scanners with multinuclear 13C imaging capability. To overcome a key operational barrier for the hyperpolarized MRI community, we propose here a radical rethinking of the requirement for multinuclear hardware on clinical scanners. Our goal is to develop hyperpolarized MRI into a clinically viable technique for the evaluation of aberrant metabolism in disease states using clinical MRI scanners that have only proton imag- ing capabilities. To this end, we will develop and build a smart cost-effective add-on module which, when used in conjunction with a polarizer for HP 13C-pyruvate production, will transfer polarization from 13C to proton and enable in vivo imaging of pyruvate metabolism on standard clinical scanner using the already available and optimized proton RF coils and imaging sequences on the scanners. If successful, the functioning prototype will be ready for evaluation in animals and directly translatable to the clinical imaging of metabolic processes.
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