An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and common malignant primary brain tumor. Patients with GBM often have poor prognoses, with a median survival of ∼15 months. Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications, the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system. This review aims to give a panoramic view of the last 3 years’ findings in glioblastoma characterization, its heterogeneity, and current advances in its treatment. Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients, including epigenetic, genetic, transcriptomic and metabolic features, as well as age‐ and sex‐related patterns and the involvement of several noncoding RNAs in glioblastoma progression. Astrocyte‐like neural stem cells and outer radial glial‐like cells from the subventricular zone have been proposed as agents involved in GBM of IDH‐wildtype origin, but this remains controversial. Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway, promotion of the glycolytic flux, maintenance of lipid storage, and other features. This metabolism also contributes to glioblastoma's resistance to conventional therapies. Tumor heterogeneity, a hallmark of GBM, has been shown to affect the genetic expression, modulation of metabolic pathways, and immune system evasion. GBM's aggressive invasion potential is modulated by cell‐to‐cell crosstalk within the tumor microenvironment and altered expressions of specific genes, such as ANXA2, GBP2, FN1, PHIP, and GLUT3. Nevertheless, the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy. Immunotherapy is still relevant for research purposes, given the amount of ongoing clinical trials based on this strategy to treat GBM, and neoantigen and nucleic acid‐based vaccines are gaining importance due to their antitumoral activity by inducing the immune response. Furthermore, there are clinical trials focused on the PI3K/Akt/mTOR axis, angiogenesis, and tumor heterogeneity for developing molecular‐targeted therapies against GBM. Other strategies, such as nanodelivery and computational models, may improve the drug pharmacokinetics and the prognosis of patients with GBM.

LINC00606 regulates glioblastoma progression by sponging miR-486-3p and interacting with ATP11B

“…In addition, using bioinformatics, we uncover that following overexpression of ATP11B in U251 cells, the DEGs are mainly enriched in the PI3K/AKT signaling pathway, which is the same as that for the target gene of miR-486-3p. The PI3K/AKT pathway is essential for the control of cell growth, and its aberrant activation is often responsible for tumorigenesis in many cancers, including glioma [50,51]. Overexpression of ATP11B and silencing of LINC00606 signi cantly inhibits the PI3K/AKT pathway and promotes apoptosis of U251 cells.…”

Transferrin receptor 1 targeted nanomedicine for brain tumor therapy

“…Invasive surgery and postoperative radiotherapy possess the most direct efficiency, while great trauma and a long-time recovery remain. 7,8 Chemotherapy as an adjuvant or major treatment is also a common way of brain tumor therapy, the mechanism of which induces direct cell death, antiangiogenesis, pro-differentiation, disruption of the tumor microenvironment and the inhibition of tumor invasion. However, the blood-brain barrier (BBB) blocks the majority of drugs from crossing and accumulating at tumor sites, resulting in a higher dosage of drugs needed to be administered to achieve effective therapeutic outcomes.…”

Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells

“…Glioblastoma (GB) is one of the most aggressive types of human cancer [ 1 ]. Despite enormous research efforts over the last decades, median overall survival still ranges between about 15 and 20 months for patients treated with radio- and chemotherapy following brain tumor surgery with or without tumor treating fields [ 2 , 3 , 4 ].…”