Prognostic Value of PFKFB3 to PFKFB4 mRNA Ratio in Patients With Primary Glioblastoma (IDH-Wildtype)

: A hallmark of glioblastoma is the high level of aerobic glycolysis. PFKFB3 and PFKFB4 are regulatory glycolytic enzymes, which are overexpressed in glioblastomas. Selective inhibition of these enzymes has emerged as a new approach in tumor therapy. We investigated the ratios of PFKFB3 to PFKFB4 mRNA expression in 66 astrocytic tumors of different malignancy grades. PFKFB3 mRNA levels were considerably higher than those of PFKFB4 in all analyzed tumors. IDH-wildtype glioblastomas showed lower PFKFB3 to PFKFB4 mRNA ratios (7.7:1) than IDH-mutant low-grade astrocytomas (36.5:1), indicating a dependency of the ratio on malignancy grade. In IDH-wildtype glioblastomas exhibiting loss of heterozygosity (LOH) of the PFKFB3 gene locus, the decrease of PFKFB3 mRNA levels was accompanied by lower PFKFB4 mRNA levels, but the PFKFB3 to PFKFB4 mRNA ratio did not differ between tumors with or without PFKFB3 LOH. IDH-wildtype primary glioblastoma patients with high PFKFB3 to PFKFB4 mRNA ratios above the average of 7.7:1 had a significantly longer overall survival time (14 months) than patients with lower ratios (9 months). Our results indicate that low PFKFB3 to PFKFB4 expression ratio is a poor prognostic factor in patients with IDH-wildtype primary glioblastoma and that PFKFB3 and PFKFB4 might represent promising targets for astrocytoma and glioblastoma treatment.