Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies

Abstract

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

Keywords: Glioblastoma multiforme; Molecular mechanisms; Signaling pathways; Targeted therapy; Therapeutic resistance.

Fig. 1

An overview of GBM progression. Key mechanisms include vessel co-option, where tumor cells utilize pre-existing vessels without inducing angiogenesis, and vessel invasion, which compromises vascular integrity and leads to neuronal hypoxia. In advanced stages, the breakdown of the BBB increases vascular permeability, facilitating tumor growth. Genetic alterations are crucial in GBM, with EGFR and PDGFR mutations promoting proliferation and angiogenesis, while IDH1 status affects prognosis. Common genetic changes, such as LOH on chromosome 10q, and mutations in PTEN, MDM2, and TERT, disrupt tumor suppression and enhance malignancy. Understanding these mechanisms is essential for the development of targeted therapies

Fig. 2

Epidemiology of GBM. This figure offers an overview of brain and CNS tumor distribution from 2014 to 2018, categorized by tumor behavior (benign or malignant) and histological type. The upper section presents the overall distribution of tumor behaviors, while the lower section focuses on malignant tumors, particularly gliomas. Additionally, the figure includes a pie chart comparing the five-year survival rates of GBM patients treated with RT alone versus those treated with a combination of radiation therapy (RT) and temozolomide (TMZ), highlighting the significant improvement in survival with the combination therapy

Fig. 3

Signaling pathways in GBM. Selected signaling pathways, such as VEGF, Wnt, NF-κB, mTOR, PI3K/AKT, and P53, are highlighted as examples of pathways studied in GBM

Fig. 4

Pie chart illustrates the prevalence of various molecular mechanisms in GBM

Fig. 5

Regorafenib targets key pathways involved in tumor progression, including stromal kinases (FGFR, PDGFR) that regulate the TME, angiogenic kinases (VEGFRs, Tie-2) critical for blood vessel formation and stabilization, and oncogenic kinases (RET, KIT) that drive tumor cell proliferation and survival. A notable mechanism of action is its inhibition of CSF-1R on macrophages, which disrupts the development and maintenance of tumor-TAMs. By targeting TAMs, regorafenib diminishes its role in promoting tumor growth and immune evasion, shifting the TME toward an anti-angiogenic and anti-proliferative state. Additionally, regorafenib’s inhibition of VEGFRs and Tie-2 enhances its anti-angiogenic effects by reducing the formation of blood vessels necessary for tumor growth and metastasis

Fig. 6

The NF-κB pathway is a pivotal target in GBM therapy. Inhibition of IκB kinase 2 or the expression of an IκBαM super-repressor reduces tumor proliferation. Amentofavone suppresses NF-κB signaling, mitigating associated risks. In the Kaplan–Meier plot, the vertical axis represents survival, while the horizontal axis indicates time. The plot includes lines for low risk, intermediate risk, and high risk groups. Individuals who are placed in the low-risk category are those in whom the inhibition of the NF-kB pathway results in a reduction in risk, placing them in the low-risk group. This suggests that the suppression of the NF-kB signaling pathway plays a protective role, reducing the risk and thus categorizing these individuals as low-risk. NF-κB inhibitors and siRNA promote apoptosis and overcome cisplatin resistance, presenting a promising therapeutic approach for GBM

Fig. 7

Targeting GSCs holds great promise for improving the efficacy of chemotherapy and immunotherapy. Pharmacological inhibition of NF-κB using PTDC (Pyrrolidinedithiocarbamate) or suppression of MYC with KJ-Pyr-9 (a small molecule inhibitor) significantly reduces GSC viability, outperforming standard chemotherapeutic agents like TMZ, even in the absence of TNFα's cytoprotective effects. Furthermore, natural killer (NK) cells offer an effective cell-based therapeutic approach by efficiently targeting and eradicating GSCs, presenting a powerful strategy to combat GBM

Fig. 8

WNT signaling is a key driver of GBM progression and resistance, influencing tumor initiation, advancement, and therapeutic response. Its role can be summarized in three main areas: (1) maintaining GBM stem cells (GSCs), (2) promoting tumor cell migration and invasion, and (3) contributing to multi-drug resistance. WNT signaling facilitates GSC self-renewal and survival in adverse microenvironments through regulators such as PLAGL2, FoxM1, and ASCL1. It enhances GBM aggressiveness by upregulating EMT-related genes like ZEB1, SNAIL, and MMPs. Furthermore, WNT signaling aids therapy resistance by allowing residual tumor cells to evade treatment, leading to recurrence. Targeting WNT signaling presents a promising avenue for overcoming GBM resistance and improving patient outcomes

Fig. 9

Telomerase reverse transcriptase in GBM. Mutations in IDH1/2 and the TERT gene contribute to the development of TERTp-WT-IDH WT GBM, playing a critical role in telomere maintenance during DNA replication—a key process in GBM progression. While there is substantial evidence supporting the involvement of TERTp mutations in GBMs, their prognostic value remains a subject of debate. Understanding the molecular mechanisms underlying TERTp-mutated GBMs could pave the way for targeted TERT-based therapies. TERT, located on chromosome 5, encodes the catalytic subunit of the telomerase complex, significantly contributing to genomic instability and tumor progression. Additionally, on the X chromosome, it drives the alternative lengthening of telomeres phenotype. These mutations create new transcription factor binding sites, enhancing TERT expression and promoting GBM progression

Fig. 10

The PI3K/AKT/mTOR pathway in GBM progression. This pathway plays a critical role in GBM progression. Elevated glucose levels increase the ATP/AMP ratio, inhibiting AMPK, which normally suppresses mTORC1. This inhibition activates mTORC1, driving protein synthesis, cell growth, and proliferation. RTKs activate PI3K, converting PIP2 to PIP3, which activates AKT, a central regulator of cell survival and growth. The loss of PTEN, a tumor suppressor, results in sustained AKT activation, leading to uncontrolled signaling. AKT promotes GBM cell survival by inhibiting apoptosis through the phosphorylation of targets such as BAD and GSK3. Under hypoxic conditions, HIF1 and VEGF interact with this pathway to enhance angiogenesis and metabolic adaptation, contributing to tumor aggressiveness. Inhibitors like TORIN and Rapalogs offer potential therapeutic strategies by targeting mTOR-dependent signaling in GBM

Fig. 11

TGF-β signaling in GBM progression. In GBM cells, upregulation of TGF-β1 and TGF-β2 activates the TGF-β signaling pathway, triggering a cascade of cellular events that drive tumor progression. This activation increases the expression of PDGF-BB and SMAD2/3, which enhance cell proliferation and tumor growth. Elevated SMAD2 and ZEB1 levels further promote tumor cell invasion, contributing to the aggressive and metastatic nature of GBM. TGF-β signaling also plays a crucial role in immune modulation by suppressing T cell activation and proliferation, reducing NK cell activity, and downregulating IL-2 production, thereby weakening the immune response and enabling tumor immune evasion. Additionally, TGF-β signaling drives M2 polarization of macrophages, leading to the secretion of immunosuppressive cytokines, which further enhance immune suppression within the TME

Fig. 12

Notch signaling in GBM progression. Notch signaling is activated through ligand-receptor interactions, where the Delta ligand binds to the Notch receptor. This binding triggers Notch cleavage by ADAM10 and Gamma-secretase, releasing the Notch Intracellular Domain (NICD). The NICD translocates to the nucleus, where it interacts with Co-Repressors (Co-R) and the CSL transcription factor to regulate the expression of target genes involved in proliferation, differentiation, and survival. In contrast, when NICD is absent, Notch signaling is inhibited, and Co-R and CSL complexes suppress gene expression. Dysregulation of this pathway is associated with elevated VEGF and pAKT levels and decreased PTEN expression, promoting tumor growth. These changes drive increased tumor cell proliferation, angiogenesis, and metastasis, contributing to the aggressive behavior of GBM

Fig. 13

Ras/MAP/ERK Pathway in GBM. This schematic illustrates the key components of the Ras/MAP/ERK pathway in GBM, including its activation mechanisms, downstream effects, contributions to tumor development, and the specific role of the Ras/RAF/ERK cascade in gliomas

Fig. 14

The high prevalence of p53 mutations in GBM underscores their potential as key targets for precision medicine therapies. Strategies to reactivate or restore wild-type (wt) p53 function hold significant promise for treating GBM and other cancers. Therapeutic approaches focus on enhancing wt-p53 activity or counteracting gain-of-function (GOF) mutant p53. These include inhibiting the MDM2/p53 interaction to prevent wt-p53 degradation, restoring wt-p53 function in tumors with mutant p53, and targeting GOF mutant p53 for degradation. Together, these strategies highlight the potential of p53-targeted therapies to improve outcomes in GBM. (To review the function of each item mentioned in the figure, please refer to the list of abbreviations provided in the article)

Fig. 15

ATM/Chk2/p53 pathway in GBM

Fig. 16

Complex and dynamic interactions between signaling pathways in shaping GBM progression, therapeutic resistance, and disease outcomes (*To draw this figure, data from the reports in references [, , , , , , –380] were used.)

Fig. 17

SHH signaling pathway in GBM, particularly in GSCs: In the absence of the hedgehog (HH) ligand, the Ptch receptor inhibits Smo, leading to the formation of GliR, a repressor that suppresses the expression of target genes. Ptch and SUFU act as critical tumor suppressors in this context. When the HH ligand binds to Ptch, it induces the receptor's degradation, relieving the inhibition on Smo. This activates a signaling cascade through Smo, resulting in the formation of GliA, a transcription factor that drives the expression of genes promoting tumor proliferation and survival. Activation of this pathway significantly enhances tumor cell proliferation, fueling cancer growth and progression