Characterization of glutamate excitotoxicity and its role in high-grade gliomas biology

Rationale This project aims to unveil the interactions of glutamate (Glut) excitotoxicity and tryptophan (TRP) metabolism derangements via the kynurenine (KP) and serotonin pathways (SP) in the interplay contributing to glioblastoma IDH-wt (GBM) invasion, immune escape, angiogenesis, and therapies response. Methods Planned enrollment of 140 patients (retrospective analyses of neuroimaging, clinical data, and biological samples from OSR-CRB Biobank + prospective enrollment and follow-up). Baseline blood levels of Glut, TRP, KP and SP mediators will be controlled against healthy controls and monitored following surgery and adjuvant therapies. Perfusion MRI data, GBM cell expression of Glut receptors and KP/SP enzymes, the extent of angiogenesis, and immune-infiltrate features will be addressed. Preliminary results (retrospective, n=62) The baseline serum levels of 5-HT, KYN, 5-HTP, and 5-HT/TRP were reduced (-76%, -87%, -76%, -75%, p<0.001) in GBM compared to controls. The median OS was shorter when Glut > 56.3mg/ml (p=0.002), 5-HT < 78ng/mL (p=0.01), KYN < 18ng/mL (p=0.004). Interestingly, circulating myeloid-derived suppressor cells (MDSC) and T-regs were inversely correlated with KYN (r=-0.51, p=0.01; r=-0.46, p=0.03), while dendritic (DC) and B cells positively correlated with 5-HT (r=0.47, p=0.02; r=0.60, p=0.003). Systemic platelet activation (MPV > 10.3·10-15L) was associated with worse OS (p=0.04). Prospective enrollment, follow-up, neuroimaging, and histological analyses are ongoing. Future directions We plan to develop a predictive model of tumoral invasiveness, immune escape, and angiogenesis based on the direction and extent of Glut-KP/SP metabolism derangement, neuroimaging, and histological features. The aim is to improve patient selection for interventions targeting these pathways, enhancing the likelihood of treatment response and survival benefit.