Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Abstract

Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood-brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets.

Keywords: B-Raf; EGFR; Met; NF-1; glioblastoma; targeted therapy.

Figure 1

Glioblastoma’s treatment timeline: in the upper part of the figure, the novel treatments under investigation are reported, while in the lower part are the approved treatments in the adjuvant and relapsed phases with a reported significant improvement in survival, i.e., STUPP and REGOMA trial, respectively, dated 2005 and 2019. The median overall survival for the experimental and control arms is also reported. The methylation of MGMT promoter is associated with improved survival compared with unmethylated subtypes. Met, methylated; unmet, unmethylated.

Figure 2

A comprehensive representation of the relevant pathways in glioblastoma.

Figure 3

Schematic representation of the hTERT gene structure and the telomerase complex. (A) Schematic mechanism of a chromosome (telomeres in orange, short arm in light blue, long arm in blue, and centromere in yellow) and the molecular mechanism through which TERT enzyme, supported by TERC, ensure the telomere length. (B) hTERT gene promoter region (in blue) and coding region (in light blue) are shown. The transcription start site (TSS) is indicated as a red bar; on the promoter region, the most common mutations which lead to an increased expression of the gene are shown (the indicated positions refer to the TSS). Shown on the left, in the light blue box, is the consensus sequence which takes place because of the single mutation, allowing the binding of the transcription factor GABP on the promoter.

Figure 4

The main oncogenic alterations of EGFR: (A) Localization of relevant alterations within the epidermal growth factor receptor (EGFR) gene in glioblastoma (GBM) and lung cancer. The structural organization of EGFR exons and respective domains is shown. The principal point mutations and deletions in GBM (in exons 1–16, extracellular domain) and in lung cancer (in exons 19–20, tyrosine kinase domain) are indicated. The frequency of intragenic deletion in exons 2 to 7 (leading to variant EGFRvIII) is indicated. (B) EGFR (left) and EGFRvIII (right) signaling pathways. EGFR and EGFRvIII trigger the AKT and MAPK pathways, but ligands (pink circles) can bind and activate only EGFR, whereas EGFRvIII is constitutively active in a ligand-independent manner. Block arrows indicate inhibition. Point arrows indicate activation. The downstream processes of the activation cascade are described.

Figure 5

Schematic view of NTRK signaling. Ligands (NGF in squares, BDNF in triangles, and NF3 in circles) and their respective receptors (TRK1/2/3) are represented. The main neurotrophic tyrosine receptor kinase (NTRK) fusion products (TRK-BCL1 and TRK-EV6) are represented as ellipticals as they do not need any ligand to be active. All the receptors trigger the MAPK pathway, leading to the indicated consequences. Two drugs, entrectinib and larotrectinib, can inhibit the NTRK aberrant forms as shown.