Noninvasive Diagnostic Assessment of Kidney Cancer Using Hyperpolarized 13C L-Tryptophan
Abstract
In kidney cancer, there is an abundance of dioxygenase enzymes, leading to increased consumption of the amino acid tryptophan and subsequently an overproduction of the immunosuppressive biochemical byproduct known as kynurenine. This abnormal tryptophan metabolism, especially the high kynurenine production, has been implicated in the poor prognosis of kidney cancer patients and thus drugs that could selectively inhibit these tryptophan dioxygenase enzymes are promising chemotherapeutic agents. Therefore, the ability to non-invasively image the bio-distribution of tryptophan and its metabolite kynurenine in renal tumors could potentially become a powerful diagnostic tool for non-invasive in vivo detection and metabolic assessment of kidney cancer. Responding to this diagnostic need, this study seeks to capitalize on the abnormal tryptophan metabolism of kidney cancer and turn it into its diagnostic Achilles’ heel. In particular, this project will utilize the emerging technology known as hyperpolarization that has the capability to enhance the magnetic resonance imaging (MRI) signals of tryptophan by >10,000-fold. The high sensitivity afforded by hyperpolarization could potentially transform tryptophan into an ultrasensitive MRI probe of this aberrant metabolic pathway for kidney cancer diagnostics. Armed with these capabilities, it is hypothesized this enhanced MRI will be able to image the expected high uptake of tryptophan in kidney tumors relative to normal renal tissues. Due to the overexpression of dioxygenase enzyme in kidney cancer, it is further hypothesized that this enhanced MRI will be able to map out the expected high production of the metabolite kynurenine across the renal tumor. This project could potentially translate the hyperpolarized tryptophan into an ultrasensitive metabolic MRI biomarker for non-invasive detection and metabolic assessment of kidney cancer without the pain and discomfort of renal biopsy. The primary innovation of this project is that hyperpolarized MRI is the only potential non-invasive imaging modality that has the required tandem of high sensitivity and superb specificity to image not only the expected high uptake of tryptophan but also the subsequent high production of kynurenine across the renal tumors. No other current technology has this capability to potentially accomplish such a feat of tracking tryptophan metabolism at the molecular level. This proposed study is based on a relatively simple concept, namely the abnormal tryptophan metabolism in renal tumors, and yet quite novel and potentially impactful in the sense that its detection by the latest MRI technology could potentially translate into a better non-invasive diagnostic arsenal for renal cancer detection and assessment. The short-term impact of this project is that, if successful, this study will provide on a basic or preclinical level an ultrasensitive MRI agent that (i) will not only non-invasively detect and locate the kidney tumor in vivo, but (ii) also reveal important metabolic information about this disease. Since tryptophan is an endogenous compound and will be administered at physiological concentrations, there is a high and real chance that this potential MRI biomarker for kidney cancer can be translated for use in the clinic. The long-term impact of this study is the diagnosis of kidney cancer in hospitals and clinics without exposure of patients to the ionizing radiation of CT scan or the pain of needle biopsy. This is potentially a much needed improvement in kidney cancer diagnostics and assessment not only for patients serving in the military, but also in the general public as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910741
Entities
People
- Lloyd Lumata
Organizations
- United States Army
- University of Texas at Dallas