Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

Abstract

Glioblastoma multiforme (GBM), a highly invasive and incurable tumor, is the humans’ foremost, commonest, and deadliest brain cancer. As in other cancers, distinct combinations of genetic alterations (GA) in GBM induce a diversity of metabolic phenotypes resulting in enhanced malignancy and altered sensitivity to current therapies. Furthermore, GA as a hallmark of cancer, dysregulated cell metabolism in GBM has been recently linked to the acquired GA. Indeed, Numerous point mutations and copy number variations have been shown to drive glioma cells’ metabolic state, affecting tumor growth and patient outcomes. Among the most common, IDH mutations, EGFR amplification, mutation, PTEN loss, and MGMT promoter mutation have emerged as key patterns associated with upregulated glycolysis and OXPHOS glutamine addiction and altered lipid metabolism in GBM. Therefore, current Advances in cancer genetic and metabolic profiling have yielded mechanistic insights into the metabolism rewiring of GBM and provided potential avenues for improved therapeutic modalities. Accordingly, actionable metabolic dependencies are currently used to design new treatments for patients with glioblastoma. Herein, we capture the current knowledge of genetic alterations in GBM, provide a detailed understanding of the alterations in metabolic pathways, and discuss their relevance in GBM therapy.

Analysis of cuproptosis-related genes in prognosis and immune infiltration in grade 4 diffuse gliomas

“…It has been reported that the cuproptosis gene is associated with the prognosis of triple-negative breast cancer [ 19 ]. In addition, it has been found that grade 4 diffuse gliomas are related to iron death, metabolism, and apoptosis [ [20] , [21] , [22] ]. However, the relationship between cuproptosis and grade 4 diffuse gliomas remains unclear.…”

The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

“…Activation of distinct metabolic routes also depend on the GBM genomic and epigenomic landscape, as specific mutations are associated with typical metabolic pathways, whilst perturbations in chromatin-remodeling enzyme activity may impact metabolic changes and vice versa. These specific topics have been extensively reviewed elsewhere [ 124 , 125 , 126 ].…”

Progress in Glioma Stem Cell Research

“…Notably, Novartis’s IDH305 focuses on IDH1 mutations, and ongoing trials in gliomas and other cancers with IDH1 R132 mutations are active (NCT02381886). Furthermore, both Forma Therapeutics’ FT2102 and Bayer’s BAY1436032 target IDH1 R132 tumors (R132X for BAY1436032), with trials actively enrolling patients across several tumor types, including GBM (NCT03684811 and NCT02746081) [ 162 ].…”