Thursday, April 18, 2024
4/18/2024
PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Recent work from our lab and others indicates that abnormal signal transduction, originating from oncogenic drivers and loss of tumor suppressors, results in heightened glycolytic flux in GBM. Correspondingly, inhibition of oncogenic signaling or downstream signal transduction pathways using targeted therapies can induce rapid and specific alterations in glycolysis, resulting in reduced tumor energetic and biosynthetic capacity, making the tumor vulnerable to further therapeutic exploitation. Such an imaging biomarker would be useful for providing unique insight into glucose metabolism and behavior, allowing clinicians to identify and ultimately exploit potential therapeutic vulnerabilities. While 18F-fluorodeoxyglucose (18F-FDG) PET imaging is an obvious candidate biomarker for imaging glycolysis as it is used ubiquitously in other cancers to monitor tumor metabolic behavior and treatment response, 18F-FDG PET uptake is a measure of overall glucose utilization, not specifically glycolysis. To overcome this ambiguity and provide more specificity for glycolysis, we propose combining standard of care 18F-FDG PET with fast pH and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI), a molecular MRI technique that can estimate both acidity from lactic acid and oxygen utilization, as well as perfusion and diffusion MRI to account for the effects of blood flow/volume and cell density. We hypothesize combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI, and diffusion MRI to create a “glycolytic index”, or GI, will allow us to accurately quantify glycolytic flux within heterogeneous tumors on widely available clinical imaging systems for use in studying glucose metabolism and response to a variety of targeted therapies in human GBM. The current study will investigate the central hypotheses that: (Aim 1) biopsied tumor tissue undergoing high levels of glycolysis via RNA expression, protein expression, and bioenergetics analyses can be reliably detected, correlates with direct measure of tissue pH, and strongly associated with a “glycolytic index” created by combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI and diffusion MRI; and (Aim 2) changes in this “glycolytic index” can be detected by perturbing glucose metabolism using a brain penetrant EGFR inhibitor specifically designed for GBM and correlate with pharmacologic alterations and alterations in glycolytic signaling in patients with IDH wild-type, EGFR amplified GBM.
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