Characterizing and therapeutically targeting pH-regulatory mechanisms in the perivascular and infiltrating niches of glioblastoma using amine CEST-EPI and a novel treatment platform

/ABSTRACT This proposal presents a research program focused on the utilization of pH imaging, surgery, and pH modulation for the treatment of infiltrative glioblastoma (GBM). Despite therapeutic advances in oncology, isocitrate dehydrogenase wild-type (IDHwt) GBM remains resistant to current treatment modalities, with median survival rarely exceeding 24 months post-diagnosis. Dysregulation of pH homeostasis, a hallmark of malignant progression extensively characterized in extracranial neoplasms, represents a promising target for both diagnostic imaging and therapeutic intervention. We have developed and validated amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI), a pH-sensitive magnetic resonance imaging technique that enables high-resolution visualization of metabolically active tumor regions through detection of extracellular acidosis in both contrast-enhancing and non-enhancing infiltrative zones of GBM. Preliminary data demonstrate CEST-EPI's enhanced sensitivity and specificity for detecting infiltrative tumor regions compared to conventional imaging modalities. This technique has enabled characterization of differential expression patterns of key pH regulatory mechanisms, including monocarboxylate transporters (MCT1/4), sodium-hydrogen exchangers (NHEs), and sodium-bicarbonate cotransporters (NBCs) across varying pH microenvironments. Based on these findings, we hypothesize that CEST-EPI-guided surgical resection targeting infiltrative tumor regions beyond conventional margins is both safe and feasible, while simultaneously providing a platform for investigating pH regulatory mechanisms in GBM. Furthermore, we propose that targeted inhibition of these mechanisms represents a novel therapeutic strategy. Our multidisciplinary research program integrates expertise across advanced neuroimaging, neurosurgical techniques, and preclinical model development to establish a novel therapeutic paradigm for targeting pH dysregulation in GBM. Successful validation of this approach could significantly improve local tumor control with potential implications for enhanced overall survival, representing a paradigm shift in the therapeutic landscape of GBM management. The combination of innovative imaging technology, molecular validation approaches, trial design, and preclinical models positions this work to significantly advance our understanding of pH regulation in glioblastoma while developing new therapeutic strategies. Success could establish a new paradigm for metabolic imaging-guided surgery and pH-targeted therapy in brain tumors. Project Number: 1R01CA309193-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kunal Patel (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $640,597 | Activity Code: R01 | Study Section: Imaging Guided Interventions and Surgery Study Section[IGIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11279294