Abstract
Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, and radiation, are palliative at best. The design of effective and targeted chemotherapeutic strategies for the treatment of GBM require a thorough analysis of specific signaling pathways to identify those serving as drivers of GBM progression and invasion. The Wnt/β-catenin and PI3K/Akt/mTOR (PAM) signaling pathways are key regulators of important biological functions that include cell proliferation, epithelial–mesenchymal transition (EMT), metabolism, and angiogenesis. Targeting specific regulatory components of the Wnt/β-catenin and PAM pathways has the potential to disrupt critical brain tumor cell functions to achieve critical advancements in alternative GBM treatment strategies to enhance the survival rate of GBM patients. In this review, we emphasize the importance of the Wnt/β-catenin and PAM pathways for GBM invasion into brain tissue and explore their potential as therapeutic targets.
Highlights
Glioblastoma multiforme (GBM) is a type of fatal primary brain tumor in adults, with a median survival duration of about 16 months
In IDH1 mutant glioma, phosphoinositol 3-kinase (PI3K)/mammalian target of rapamycin suppression led to decreased production of the oncometabolite 2-hydroxyglutarate (2HG), and this is associated with improved survival [17]
epidermal growth factor receptor (EGFR)/PI3K/mammalian target of rapamycin (mTOR) inhibitory compounds as well as drugs targeting the Wnt/β-catenin signaling pathways utilized in preclinical and/or clinical investigations for glioma treatment were adapted from [122,123] review papers, respectively
Summary
Glioblastoma multiforme (GBM) is a type of fatal primary brain tumor in adults, with a median survival duration of about 16 months. Over the previous three decades, survival rates for patients diagnosed with GBM have improved by a mere three months This is due to the locally aggressive and invasive nature of GBM, the ability of GBM cells to develop therapeutic resistance, and the limited number of drugs capable of reaching therapeutic concentrations in the brain [1,2]. In primary GBM cells, active Wnt/β-catenin signaling increases the expression of EMT activators such as zinc-finger E-box binding homeobox 1 (ZEB1), twist-related protein 1 (TWIST1), and snail-related zinc-finger transcription factor (SLUG1), and promotes the in vitro migration capacity [9,10,11,12]. Active Wnt/β-catenin signaling has been associated with decreased GBM patient survival. Combining PI3K inhibitors with drugs blocking these pathways may promote GBM apoptosis
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