Dual Metabolic Biomarker for Noninvasive Diagnostic Assessment and Imaging of Renal Cancer
Abstract
Despite recent medical advances, renal cell carcinoma remains in the top ten most prevalent malignancies in the world and has exhibited an overall increase in the number of cases over the last decade. Clearly, there are unmet clinical needs both in the therapeutic and diagnostic fronts in the battle against kidney cancer as the average survival rate of renal cancer patients has not significantly improved. It is apparent that kidney cancer is a multifaceted disease that needs to be strategically approached on all fronts and research should leave no stone unturned in terms of understanding and discovering its therapeutic and diagnostic vulnerabilities. This study seeks to advance kidney cancer diagnostics by using the latest technology in magnetic resonance imaging (MRI) and selecting a strategic biochemical marker to diagnostically target not only the detection of urea cycle dysregulation in renal tumors but also the hyperdrive polyamine production in renal cancer. The objective of this proposal is to identify and develop new strategies for screening, early-stage detection, and accurate diagnosis and prognosis prediction of kidney cancers, specifically with using metabolic biomarkers and imaging. This research project seeks to turn the aberrant biochemistry in kidney cancer, namely the downregulated urea cycle and hyperdrive polyamine biochemical production, into a diagnostic advantage by using the latest MRI technology available today. The urea cycle is the main pathway by which the mammalian cells dispose of toxic ammonia waste products. Converting ammonia into urea is also one of the foremost functions of a healthy kidney and thus the observed repression of the urea cycle in kidney cancer is a prominent telltale sign of this disease. Meanwhile, the amino acid ornithine is also a precursor molecule for the neighboring biochemical pathway for polyamine production. Polyamine (a raw material for multiple cellular biosynthetic processes) production is in hyperdrive in kidney cancer to sustain the voracious appetite of rapidly proliferating renal cancer cells. It should be noted that tracking ornithine metabolism in vivo, say in murine models of renal cancer, is next to impossible to detect via conventional MRI due to the large water background signal and the inherent insensitivity of nuclei such as carbon-13. However, by employing the dissolution dynamic nuclear polarization technology in this project, the inherent MRI sensitivity issue of carbon-13 tracers is overcome, in fact, to an unprecedented level of >10,000-fold in terms of enhancement. Such sensitivity amplification provides an opportunity to use a single metabolic tracer, in this case hyperpolarized 13C-ornithine, as a probe with dual biomarkers for kidney cancer: downregulated UC activity and upregulated polyamine synthesis. The main advantage of this project is that the proposed diagnostic agent is itself one of the UC metabolites and a precursor molecule for polyamine production, thus bio-compatible, and as such, this metabolic spy can naturally and safely infiltrate into the targeted metabolic pathways in vivo.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210105
Entities
People
- Lloyd Lumata
Organizations
- United States Army
- University of Texas at Dallas