Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

Abstract

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

Keywords: clinical trials; diagnosis; glioblastoma; therapy.

Fig. 1

Glioblastoma. (A) Incidence rate per 100 000 persons by age at diagnosis and sex, Central Brain Tumor Registry of the United States (CBTRUS) 2012–1016 (50 US states and Puerto Rico included) and (B) 5-year relative survival probability (with 95% confidence intervals) by age at diagnosis and sex, National Program of Cancer Registries (NPCR) 2012–2016 (43 US states included). **Glioblastoma defined by International Classification of Disease-Oncology (ICD-O) version 3 codes 9440/3, 9441/3, 9442/3.

Fig. 2

Glioblastomas are characterized by somatic molecular defects in 3 major processes: initiating tumor growth, evading senescence and enabling immortal growth. Genomic abnormalities in each of the 3 processes appear required for gliomagenesis. The 3 processes are shown here, as are some of the most frequently altered genes and pathways.

Fig. 3

The many forms of GBM. (A) Classic GBM, with pseudopalisading necrosis and microvascular proliferation. (B) Giant cell GBM. (C) Epithelioid GBM with BRAF V600E. (D) Gliosarcoma. (E) Granular cell GBM. (F) Small cell GBM. All images are from the UPMC Neuropathology Virtual Slide Database, 200x magnification.

Fig. 4

Sixty-four-year-old with a glioblastoma who presented with word finding difficulty. FLAIR (A) and contrast-enhanced T1W (B) images show a large, necrotic-appearing, enhancing mass with surrounding T2/FLAIR signal abnormality in the periventricular regions. There is evidence of hypercellularity on ADC map (black arrow in C) and elevated blood volume on CBV map (white arrow in D)

Fig. 5

Contrast-enhanced MRI T1W (left) and ¹⁸FET-PET (right) of a 42-year-old patient showing much larger extent of a glioblastoma on the PET images compared with the enhancing tumor evident by MRI. The tumor extent on the PET image was confirmed by histology.

Fig. 6

Standard of care treatment paradigm for newly diagnosed glioblastoma.

Fig. 7

Standard of care treatment paradigm for recurrent glioblastoma.

Fig. 8

Microsurgical resection of a right-sided recurrent IDHwt glioblastoma WHO grade IV using intraoperative neuronavigation, neuromonitoring and 5-ALA fluorescence techniques. (A) T1 contrast enhanced axial, sagittal and coronal planes including DTI fiber tracking (blue fibers). The green trajectories/red points represent the pointer for intraoperative neuronavigation. (B) Upper image: corresponding intraoperative 5-ALA fluorescence image taken from the area as depicted by neuronavigation. Lower image: opening of the right ventricle due to critical involvement by tumor formation. (C) Postoperative MRI confirms gross total resection without residual contrast enhancement, no perilesional ischemia (diffusion-weighted image upper right).

Fig. 9

This figure shows, from left to right, how the transition from 2D RT to 3D RT to intensity modulated radiotherapy to intensity modulated proton therapy harnesses the potential for sparing normal, uninvolved brain substructures from unnecessary RT dose; whether this produces meaningful patient clinical benefit is a subject of current clinical trial testing.

Fig. 10

Selected recently completed or ongoing trials with targeted molecular therapies. CDK = cyclin-dependent kinase; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; FGFR = fibroblast growth factor receptor; GF = growth factor; HDAC = histone deacetylase; HSP = heat shock protein; MDM2 = murine double minute 2; mTOR = mammalian target of rapamycin; PARP = poly(ADP-ribose) polymerase; PDGFR = platelet derived growth factor receptor; PKC = protein kinase C; RTK = receptor tyrosine kinase; TGF-β = transforming growth factor beta; TGFβR = transforming growth factor beta receptor; TrK = tropomyosin receptor kinase; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; XPO1 = exportin 1.

Fig. 11

A simplified overview of signaling from common types of DNA damage to the DDR and cell cycle checkpoint pathways. Initial damage is sensed by proteins including the histone γ -H2AX, which is rapidly phosphorylated by ATM at a specific serine residue in response to chromatin structure alteration at DBS sites, activating recruitment of repair proteins including BRCA1 and the MRN complex (MRE11, Rad51, NBS1). DSB repair is undertaken by the end-joining pathway involving the kinase DNA-PK and Ku protein binding partners and the homologous recombination pathway involving Rad51 and associated proteins. Single strand breaks (SSB) and replication stress leading to stalled replication forks activate PARP which in turn recruits repair factors including XRCC1 and promotes chromatin remodeling at the break site and base excision repair. ATR and ATM function both in the initial signaling cascade and as transducers to downstream activation of the cell cycle checkpoints inhibitors, Chk1 and Chk2 producing cell cycle delay to facilitate repair. Points in the pathway at which specific inhibitors are available are indicated. As predicted from their roles in the DDR pathway, ATM and ATR inhibitors sensitize to a broad range of DNA damaging agents causing single or double strand breaks. PARPi and cell cycle checkpoint inhibitors including Wee1 inhibitors are specifically effective in cells undergoing rapid replication. DSB = Double Strand Break; SSB = Single Strand Break.

Fig. 12

An expanded pharmacopoeia of metabolic drug targets in glioblastoma (Adapted with permission from Bi et al. Nature Rev Cancer 2020;20:57–70.) The extensive focus on altered glioma metabolism has led to a considerable expansion in the list of potential drug targets. Receptor tyrosine kinase (RTK)-driven metabolic dependencies have also been identified. For example, epidermal growth factor receptor (EGFR) amplification produces major changes in metabolic enzyme dependencies, including in glucose uptake, glycolysis, fatty acid (FA) synthesis, membrane lipid remodeling, cholesterol uptake, NAD+ production and epigenetic remodeling. Targeting lysophosphatidylcholine (LysoPC) acyltransferase 1 (LPCAT1) decreases the level of saturated phosphatidylcholines (PCs) and disrupts plasma membrane localization of EGFR variant III (EGFRvIII), which blocks EGFRvIII- driven oncogenic signaling and suppresses glioblastoma (GBM) tumor growth. LXR-623, a brain- penetrant liver X receptor (LXR) agonist, targets the cholesterol homeostasis of GBM cells by promoting ATP- binding cassette subfamily A member 1 (ABCA1)-mediated cholesterol efflux and inhibiting low- density lipoprotein receptor (LDLR)-mediated cholesterol uptake. Isocitrate dehydrogenase (IDH) mutants in glioma cells generate the oncometabolite d-2-hydroxyglutarate (D2HG), which defines the dependencies of NAD+ and glutathione (GSH) production and impacts epigenetic events in glioma cells. The oxidative phosphorylation (OXPHOS) inhibitors, including metformin, Gboxin and IACS-010759, target glioma cells by inhibiting transmembrane protein complexes in the mitochondrial inner membrane, known as the electron transport chain (ETC). 2DG, 2-deoxy-d-glucose; 2PG, 2-phosphoglyceric acid; αKG, α-ketoglutarate; ACBP, acyl-CoA-binding protein; ACLY, ATP citrate lyase; ACSS2, acetyl-CoA synthetase; AMPK, AMP-activated protein kinase; BCAA, branched-chain amino acid; BCAT1, branched- chain amino acid transaminase 1; BCKA, branched-chain keto acid; BRD4, bromodomain containing 4; DCA, dichloroacetate; ELOVL2, ELOVL FA elongase 2; FASN, FA synthase; GDH1, glutamate dehydrogenase 1; GLS, glutaminase; GLUT1, glucose transporter 1; HSPD1, heat shock protein family D (Hsp60) member 1; IDH1, isocitrate dehydrogenase 1; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter 1; NA, nicotinic acid; NAMPT, nicotinamide phosphoribosyl-transferase; NAPRT1, nicotinate phosphoribosyltransferase domain containing 1; NM, nicotinamide; PDK, pyruvate dehydrogenase kinase; PEP, 2-phosphoenolpyruvate; PKM2, pyruvate kinase muscle isozyme M2; SHMT1, serine hydroxymethyltransferase 1; TCA, tricarboxylic acid; xCT, cystine/glutamate transporter. Reproduced with permission from Bi J, et al.

Figure 13.

Challenges to effectively treat GBM include (top) the presence of the blood–brain barrier that precludes the delivery of many drugs into the brain coupled to (middle) an immunosuppressive microenvironment and (bottom) compensatory signaling networks that can render GBM therapies ineffective.