NIMG-34. QUANTIFICATION OF GLYCOLYTIC FLUX REDUCTION IN RECURRENT GLIOBLASTOMA AFTER EGFR INHIBITION USING MOLECULAR MR-PET

Abstract

Abstract In recently published work, we demonstrated that acute inhibition of the EGFR – the most frequently altered oncogene in GBM – can rapidly reduce glycolysis in a subset of GBM. To quantify this effect, we propose a new combination metabolic MR-PET imaging biomarker that combines 18F-FDG PET, DSC perfusion MRI, diffusion MRI, and pH- and oxygen-sensitive amine CEST-SAGE-EPI. Specifically, this “glycolytic index” or GI, can be defined as elevated glucose uptake (18F-FDG standard uptake value), elevated tumor acidity (MTRasym@3ppm), and lower oxygen utilization (relative cerebral metabolic rate of oxygen, rCMRO2, defined as R2’ x rCBF/rCBV from oxygen-sensitive SAGE-EPI and DSC perfusion), normalized to cell density (using ADC from diffusion MRI). In the current study, we explored the use of Tagrisso® (Osimertinib or AZD9291), which has very high brain to plasma ratios (> 1) and has proven effective in CNS metastasis of EGFR mutant lung cancer, as a potential treatment for EGFR amplified recurrent GBM. We have conducted a clinical trial (NCT03732352) to determine whether we observe similar metabolic imaging changes in EGFR mutated or amplified recurrent glioblastoma patients after treatment with osimertinib. Consistent with prior in vitro and in vivo results, treated patients exhibited a reduced glycolytic flux as indicated by reduction in 18F-FDG PET uptake (-3% change in SUV), tumor acidity (-19% change in MTRasym@3ppm) on pH-weighted CEST MRI, and glycolytic index (GI) (-25% change) in EGFR amplified recurrent GBM within 24 hours of treatment. Preliminary data suggests early change in GI correlates with and predicts both PFS (Pearson correlation, R2=0.3463, P=0.0441; Log-rank, P=0.0467) and OS (R2=0.6368, P=0.0019; Log-rank, P=0.0192). These preliminary data establish the scientific premise that a “glycolytic index” created using 18F-FDG PET, DSC perfusion, diffusion MRI, and pH- and oxygen-weighted amine CEST-SAGE-EPI may be an important tool for quantifying and visualizing glycolytic flux in GBM.