Development and Translation of D-glucose as a Diagnostic Agent for MRI of Cancer

PROJECT SUMMARY/ABSTRACT Annually, about 50,000,000 doses of synthetic gadolinium imaging contrast agents are injected into patients worldwide when getting an MRI. While these agents are extremely safe, they have the potential for adverse effects in some patients. Also, they may accumulate in brain and bone tissues when a procedure is repeated, with yet unknown risks. Currently, all MRI agents require some kind of chemical labeling, i.e. with para- or ferro-magnetic metals or, recently, with hyperpolarized magnetic isotopes. The overall goal of this BRG is the development of simple D-glucose as an MRI contrast agent. Advantages of using such a natural agent are safety, absence of interference with contrast on standard anatomical images, low cost, and the ability to perform repeated studies over a short period of time. We will first develop this technology for brain cancer, after which it can be adjusted for general use. Contrast agents are used to visualize tumor anatomy and physiology, which can provide information on malignancy and the response to treatment. Our hypothesis is that D-glucose as an infusible MRI contrast agent can provide information on three important aspects of tumor physiology, namely delivery, uptake (including effects of blood brain barrier disruption), and metabolism. If our developments are successful, translation to clinical application will be fast since D-glucose is already widely used for other indications (e.g. glucose tolerance test for diabetes), and its safety profile is well established. Our preliminary data show MRI detectability of D-glucose at millimolar concentrations in animal models at 11.7T and in brain tumor patients at 7T and 3T. However, there are technical issues at 3T due to the reduced effect size, requiring additional technology development for motion correction, data acquisition, and analysis. Our overall development goal for this BRG is to optimize and standardize the use of D-glucose as an infusible contrast agent for diagnostic and prognostic imaging of tumor physiology at the clinical field strength of 3T. The specific aims are (1) Design and optimize fast whole-brain dynamic MRI saturation pulse sequence technology to detect D-glucose based (a) T2 relaxation effects, (b) combined chemical exchange saturation transfer (CEST) and T2 relaxation effects; (2) Design and optimize CEST-MRI-compatible motion correction methods for dynamic scanning including navigator echo guidance and deep learning analysis; (3) Design and optimize semi-quantitative and quantitative data analysis approaches for visualizing tumor enhancement and obtaining indicators of tumor D-glucose delivery, uptake, and metabolism; (4) Standardize the methods of aims 1-3 and demonstrate repeatability and reproducibility to conclude the work with a clinical MRI protocol for dynamic glucose-enhanced (DGE) MRI. To accomplish these aims with optimal efficiency, proper validation and clinical relevance, we have established a multidisciplinary team of experts in the fields of MRI physics (pulse sequence development), clinical oncology, biostatistics, and endocrinology, which will employ the facilities of several Resource Centers available at Kennedy Krieger Institute and Johns Hopkins University.