Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update

Abstract

Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy are still challenging. Moreover, tumor recurrence is associated with the onset of therapy resistance; it is therefore critical to identify effective and well-tolerated pharmacological approaches capable of inducing durable responses in the appropriate patient groups. Molecular alterations of the RTK/PI3K/Akt/mTOR signaling pathway are typical hallmarks of glioma, and several clinical trials targeting one or more players of this axis have been launched, showing disappointing results so far, due to the scarce BBB permeability of certain compounds or to the occurrence of resistance/tolerance mechanisms. However, as RTK/PI3K/mTOR is one of the pivotal pathways regulating cell growth and survival in cancer biology, targeting still remains a strong rationale for developing strategies against gliomas. Future rigorous clinical studies, aimed at addressing the tumor heterogeneity, the interaction with the microenvironment, as well as diverse posology adjustments, are needed—which might unravel the therapeutic efficacy and response prediction of an RTK/PI3K/mTOR-based approach.

RNA m1A Methyltransferase TRMT6 Predicts Poorer Prognosis and Promotes Malignant Behavior in Glioma

“…Then, systematic bioinformatics analysis showed that cell cycle, PI3K-AKT, TGF-beta, MTORC1, NOTCH, and MYC pathways were significantly enriched in high-TRMT6 expression patients. Consistently, many studies have demonstrated that the activation of the cell cycle, PI3K-AKT, MTORC1, NOTCH, and MYC pathways enhances the progression of glioma (Parmigiani et al, 2020;Colardo and Segatto, 2021;Hajj et al, 2021). Notably, previously published literature has shown that TGF-beta ligands and its receptors exhibited low expression in low-grade gliomas (Yamada et al, 1995).…”

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

“…Therefore, the role of FOXO1 in metabolism in U87MG cells is complex. In line with the positive impact of FOXO1 on LDHA , FOXO factors can be associated with cancer-promoting activities and even cause resistance to Temozolomide (TMZ) [ 17 , 44 , 45 ]. Previous reports have shown that a FOXO1 homolog (FOXO3) contributed TMZ resistance in GBM through promoting beta-catenin nuclear localization [ 45 ].…”

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

“…13 S3). 13 10-Hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(((S)-1-phenylethyl)amino)methyl]-1,2,3,4, 4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid (12). Compound 12 was obtained through the reaction with (S)-1-phenylethanamine as a white solid (31 mg, 22%); mp 240-243 • C. 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.33-7.29 (m, 4H), 7.22-7.20 (m, 1H), 5.15 (s, 1H), 3.58 (q, J = 6.6 Hz, 1H), 2.74 (dd, J = 13.5, 4.4 Hz, 1H), 2.58 (d, J = 12.0 Hz, 1H), 1.91 (d, J = 12.0 Hz, 2H), 1.80 (dd, J = 7.5, 3.1 Hz, 1H), 1.66-0.99 (m, 20H), 1.26 (d, J = 6.6 Hz, 3H), 1.11 (s, 3H), 0.88 (s, 6H), 0.85 (s, 3H), 0.68 (s, 3H), 0.63 (s, 3H) (Figure S5).…”

“…The efficacy of anti-glioma chemotherapy is limited because of poor drug delivery and inherent chemoresistance [3] or acquired chemoresistance (e.g., to TMZ) after initial treatment [12]. Due to unfavorable pharmacokinetics of chemotherapeutic drugs, poor drug delivery across the blood-brain barrier (BBB) and blood-tumor barrier (BTB) prevents them from exerting their therapeutic action properly.…”

“…The overexpression of EGFR and/or its constitutively activated variant EGFRvIII contributes to the pathogenesis of many types of cancer including GBM [16,17]. Aberrant EGFR signaling leads to poor prognosis and low survival rates for GBM patients, poor responses to therapy, and earlier recurrence after treatment [13,17] and therefore EGFR-targeted therapy has emerged as a promising approach for the management of gliomas [12][13][14][15][16][17][18].…”