Principles in the Management of Glioblastoma

Abstract

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (IDH), methylation of O⁶-methylguanine-DNA methyltransferase (MGMT), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene MGMT predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future.

Keywords: genetic and epigenetic biomarkers; glioblastoma; liquid biopsies; mutations; signaling pathways; target therapies.

Figure 1

Simplified schematic representation of the PI3K/AKT/mTOR, RAS/RAF/MAPK, RB and p53 pathways and how they interact. The activation of the PI3K/AKT/mTOR and RAS/RAF/MAPK pathways by the binding of growth factors to the RTKs plays an important role in cell proliferation. MDM2 and MDM4 are negative regulators of p53. p14 inhibits MDM2, contributing to p53 expression. These pathways interact in different ways, highlighting potential targets of therapeutic intervention. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 2

Non-coding RNAs (ncRNAs) classification and some lncRNAs and miRNAS with oncogenic (blue) and tumor suppressor (green) potential in glioblastoma. Housekeeping ncRNAs include transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA). Regulatory RNAs include long non-coding RNAs and small non-coding RNAs. MicroRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and tRNA-derived small RNAs (tsRNAs) are small non-coding RNAs.

Figure 3

Glioblastoma management overview. Glioblastoma diagnosis is based on MRI and biopsy samples. Current standard treatment consists of maximal surgical resection followed by radiation and adjuvant TMZ. Liquid biopsy emerges as a promising tool in the management of this disease, ultimately contributing to the development of targeted therapies. Parts of the figure were drawn using Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License.

Figure 4

Contrast-enhanced MRI of a glioblastoma. (a) Contrast-enhanced T1 image.; (b) T2 image showing oedema.

Figure 5

(a) Isodose distribution first course to 40 Gy intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) radiation technique; (b) isodose distribution boost dose to 60 Gy (IMRT)/(VMAT) radiation technique.