Serum p-Cresol and 7-HOCA Levels and Fatty Acid and Purine Metabolism Are Associated with Survival, Progression, and Molecular Classification in GB—Serum Proteome and Metabolome Analysis Pre vs. Post Up-Front Chemoirradiation

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Background: Glioblastoma (GB) is the most common primary brain tumor, with poor prognosis, significant neurological symptoms, and near-universal recurrence. Biomarker development is often limited by the scarcity of tumor tissue available for study. Noninvasive serum-based profiling offers potential to improve outcomes. Purpose: This study examined serum proteomic and metabolomic profiles pre- and post-concurrent chemoirradiation (CRT) to identify associations with patient outcomes and molecular classification, and to explore relevant signaling and metabolic pathways. Methods: Serum samples from 109 GB patients, obtained prior to and following completion of CRT, were analyzed with each patient serving as their own control, using a SOMAScan® proteomic assay (7289 proteins) and metabolomics (SECIM, 6015 compounds). Clinical data were obtained through chart review. Proteomic and metabolomic changes were examined at baseline (prior to CRT) and in alteration (pre- vs. post-CRT) for their association with overall survival (OS), progression-free survival (PFS), MGMT, and IDH status. Cox models, gene set enrichment analysis (Hallmark, GSEA), and Kaplan–Meier survival analysis were used. Results: Several hundred proteins and metabolites were associated with OS and PFS. MGMT status was known in 60% and IDH in 38% of patients. Pre-CRT DLST (HR 11.7, p < 0.001, adj p = 0.01) was the only protein significantly associated with OS. Pre-CRT, and higher 7-HOCA was linked to worse OS (HR 1.3) and PFS (HR 1.5), while increased p-cresol was associated with improved OS (HR 0.8) and PFS (HR 0.9). Kaplan–Meier analysis based on signal alteration post-CRT vs. pre-CRT, revealed superior OS with lower DLST and MSR1 and superior PFS with higher PGAM2 and ATG5, and lower 7-HOCA. Pathway analysis linked improved PFS to fatty acid metabolism, citric acid cycle, and purine biosynthesis. MGMT and IDH class comparisons revealed associations primarily with amino acid and fatty acid metabolism. Both MGMT methylation and IDH mutation correlated with increased PLAG12B expression, with significance only for MGMT (p < 0.001). IDH mutation was associated with decreased MSR1 (p = 0.047) and p-cresol (p < 0.001). Conclusions: Serum-based fatty acid and purine metabolism pathways are associated with OS and PFS in GB. 7-HOCA and p-cresol emerged as potential biomarkers linked to treatment response and molecular subtype. These findings support further investigation of noninvasive biospecimens for clinically actionable biomarkers in GB.

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