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Rocchi, A.;  Wollebo, H.S.;  Khalili, K. Standard of Care for Glioblastoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/27148 (accessed on 08 July 2025).
Rocchi A,  Wollebo HS,  Khalili K. Standard of Care for Glioblastoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/27148. Accessed July 08, 2025.
Rocchi, Angela, Hassen S. Wollebo, Kamel Khalili. "Standard of Care for Glioblastoma" Encyclopedia, https://encyclopedia.pub/entry/27148 (accessed July 08, 2025).
Rocchi, A.,  Wollebo, H.S., & Khalili, K. (2022, September 14). Standard of Care for Glioblastoma. In Encyclopedia. https://encyclopedia.pub/entry/27148
Rocchi, Angela, et al. "Standard of Care for Glioblastoma." Encyclopedia. Web. 14 September, 2022.
Standard of Care for Glioblastoma
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23179734

The most common, most rapidly progressing central nervous system tumor, glioblastoma, is a heterogeneous cancer with both interpatient and intratumor variability.

glioblastoma proteostasis apoptosis

1. Glioblastoma

Although the presentation and pathogenesis of each glioblastoma varies, there are several key flaws that must exist for abnormalities to become disease. PQC oversight in a healthy system quickly addresses genomic and proteomic errors as they occur.
The most common, most rapidly progressing central nervous system tumor, glioblastoma, is a heterogeneous cancer with both interpatient and intratumor variability [1][2]. This diversity has complicated the development of definitive models of both disease course and treatment [3][4]. While some radiographic and hematologic tests have been validated to assess patient prognosis, no clinical test has replaced diagnosis via invasive biopsy.

2. Diagnosis

The incidence of primary glioblastoma increases with advanced age and is higher in the male gender, whereas secondary GBM has been observed in patients with a history of radiation therapy, metastasis, and/or tumorigenic disorders (i.e., neurofibromatosis) [5][6][7]. The most common chief complaints on initial presentation are cognitive impairment and/or seizure [8]. Over the course of the disease, symptoms expand to include motor and sensory dysfunction, drowsiness/fatigue, and headache. Reports of gastrointestinal distress, alopecia, and anorexia increase during systemic treatments (i.e., temozolomide). During end-of-life care, symptoms of dysphagia, dyspnea, and confusion significantly increase in prevalence beyond those of non-GBM palliative-care patients.
GBM diagnosis is made using the WHO classification system—four stepwise criteria of histological and molecular characterization (Figure 1) [9]. Progenitor cell lines of astrocyte or oligodendrocyte origin are identified by exclusionary proteotyping. Only 10–12% of gliomas exhibit mutated IDH resulting in the impaired decarboxylation of isocitrate to αketoglutarate [10][11][12]. This arrest of the Krebs cycle leads to the toxic accumulation of reactive oxygen species, reducing cancer cell resiliency and improving patient prognosis regardless of histology. Mutated samples are therefore excluded from GBM classification.
Figure 1. Shown are the 2021 WHO classification criteria for glioblastoma. In order of increasing specificity (top to bottom): (1) Biopsy assessment begins with the identification of the glial progenitor cell line. (2) Cells with mutant IDH are excluded. (3) Tumors with necrosis or MVP on histology are grade 4 and diagnosed as glioblastoma. Three mutations are also included in the GBM diagnosis, regardless of histology: the addition of a whole chromosome 7 in the absence of chromosome 10, TERT activation or EFGR gain of function [9].
Patients with wild-type IDH require further histologic and molecular investigation.
GBM classically presents with the highest histologic grade—WHO grade 4—defined by the presence of undifferentiated glia with necrosis and/or microvascular proliferation [9]. Tumors with lower grades 2 and 3—which exhibit poor differentiation but lack necrosis and angiogenesis—are upgraded to GBM if any of three mutations are present: a gain-of-function-mutation in the EGFR promoter, the addition of chromosome 7 in conjunction with the absence of chromosome 10 (+7/−10), and/or the activation of TERT.
EGFR is a transmembrane tyrosine kinase which, when bound by its ligand EGF, initiates the Ras proliferative cascade [13]. EGFR gain-of-function mutations are present in an estimated 45% of GBM [6]. The presence of an extra copy of chromosome 7 has been correlated with the aggressiveness of glioblastomas with increased expression of the mitogens BRAF, EGFR, HOX5A, MET, and PDGFA [13][14][15][16]. Conversely, the loss of chromosome 10 includes the loss of key regulatory genes which promote the tumor-suppressing genes p53, PTEN, and SMAD3/4 and inhibit the tumorigenic gene p52 [16][17][18]. Combined, the +7/−10 pair results in aggressively upregulated cell growth in the absence of tumor suppression. Gain-of-function mutations in TERT enable the ribonucleoprotein polymerase to maintain telomeres, preventing cell senescence and prolonging a cell’s ability to replicate [19]. Any of the two histologic (necrosis, MVP) or three molecular (EGFR, +7/−10, TERT) markers upgrade “IDH wild-type diffuse glioma” to GBM.

3. Pathogenesis

No single mutation, risk factor, or environmental insult has been causatively linked to GBM onset; however, the pathogenesis of GBM does follow the classic cancer pattern of overexpressed oncogenes and/or under-expressed tumor suppressors (Table 1) [6]. Research in the TCGA identified 12 mutation sites across three regulatory cell cycle cascades. It was found that 73% of all GBM samples displayed mutations in all three pathways, suggesting that the common flaw leading to disease onset is regulatory in nature.
Table 1. Prevalence of oncogenic mutations and expression abnormalities in glioblastoma biopsy samples in the Cancer Genome Atlas.

Mutation

Prevalence

Impact

Ras proliferation

88%

Mitosis

 EGFR *

45%

 Amplification of growth receptor

 PTEN *

36%

 Deletion of P13K inhibitor

 NF1

23%

 Silencing/deletion of Ras suppressor

 PI3K

15%

 PI3K gain of function

 PDGFRA *

13%

 Amplification of growth receptor

p53 tumor suppression

87%

Persistence of oncogenes

 ARF

49%

 Deletion of p53 dis-inhibitor

 p53

35%

 p53 silencing/deletion

 MDM2

14%

 Amplification of p53 suppressor

Rb tumor suppression

78%

Disinhibition of G1/S progression

 CDK N2A

52%

 Deletion of Rb dis-inhibitor

 CDK N2B

47%

 Deletion of Rb dis-inhibitor

 CDK4

18%

 Amplification of Rb inhibitor

 Rb

11%

 Deletion of Rb
* Associated with an increase in grade of glioblastoma secondary to +7/−10 chromosomal abnormality.
The “pre-metastatic niche” refers to the conversion of a cell’s normal environment into an oncogenic haven [20][21]. Ischemia-induced growth factors promote angiogenesis, while HSF1/Wnt promote fibroblast activation, remodeling of the extracellular matrix, bone marrow production of pro-tumorigenic macrophages, and immunosuppression of anti-tumor lymphocytes [22][23][24].
Although GBM tumors rarely metastasize outside of the CNS, they regularly expand to infect surrounding tissue through oncosomes [25][26]. In addition to transforming the extracellular environment into a pre-metastatic niche, oncosomes enable the infection of intracellular environments of healthy, or less aggressive cancer, cells via macroautophagy. DNA and mRNA have been observed transferring oncogene mutations from cancerous to healthy cells [27]. Proteins, miRNA, and SNPs within exosomes enable the transfer of the proteomic and epigenetic state of tumor cells, advancing the timeline of recipient cell pathology [28][29][30].

4. Standard of Care

With a five-year survival rate of 5–7% and an average untreated life expectancy of three months, GBM is the third deadliest cancer [31]. This is exacerbated by a non-specific standard of care for what is a significantly individualized pathology [8][31]. First-line therapies raise the average life expectancy by 3 to 11 months, with more than 90% of the patients experiencing recurrence within 6 months of treatment [32][33].
The optimal treatment consists in surgical resection, typically at the time of biopsy, followed by concomitant radiation/chemotherapy and adjuvant therapy with temozolomide ± bevacizumab [33]. Surgical resection of the tumor provides decompressive therapy and slows the progression of GBM invasion by removing the primary insult of the niche. Radiation damages tumor cell DNA, impairing tumor hyperproliferation. Similarly, temozolomide is a DNA-alkylating agent which prevents mitosis by impairing the progression from phase G1 to S [34]. Bevacizumab is a vascular endothelial growth factor antagonist and impairs vascularization, key to tumor sustenance [35].
Modern advancements in epigenetics have the potential to develop the individualized patient care needed to address the uniquities of GBM. Most notably, the epigenetic inactivation of MGMT via methylation of its promoter is necessary for temozolomide sensitivity [36][37]. MGMT is a key DNA mismatch repair protein, the absence of which ensures damage from DNA alkylation will result in cell death.
The molecular investigation of GBM is not standard practice [7][38]. Given the variability of GBM presentation, the ability of multiple neural cell types to exist within one tumor, the consistency of mutation types between recurrences, and the nearly inevitable likelihood of recurrence, the epigenetic interpretation of biopsy samples could improve the current diagnostic model to account for GBM heterogeneity and promote targeted treatments more effectively [39][40].

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Subjects: Oncology
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Angela Rocchi
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Hassen S. Wollebo
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Kamel Khalili
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Update Date: 14 Sep 2022
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