Table 3 Various targeted therapies for gliomas, summarizing their mechanisms, clinical findings, limitations, emerging strategies, and future directions.

RTKs pathway inhibitors

Inhibit receptor tyrosine kinases (RTKs) like EGFR, VEGFR, which are involved in cell proliferation and angiogenesis.

EGFR inhibitors (e.g., erlotinib, gefitinib) largely ineffective in HGGs. Bevacizumab approved for recurrent glioblastoma due to imaging improvements but no survival benefit in Phase III trials.

Poor CNS drug penetration, absence of necessary mutations for therapeutic response, toxicity issues.

Development of next-generation inhibitors with better CNS penetration and specificity for mutated RTKs.

Continued research to develop inhibitors that can cross the blood-brain barrier effectively and target specific mutations. Potential for combinational therapies to overcome resistance mechanisms.

[6,7,8,9,10,11,12,13,14]

PI3K/AKT/mTOR pathway inhibitors

Target PI3K pathway alterations affecting downstream effectors like AKT and mTOR, critical for cell survival and metabolism.

First-gen mTOR inhibitors (e.g., everolimus) demonstrated antitumor activity in vitro/in vivo but no significant impact on survival in clinical trials. Dual inhibitors (e.g., sapanisertib) currently under investigation.

Limited clinical efficacy, need for improved drug formulations for better CNS penetration, and optimized combinations for enhanced therapeutic effect.

Exploring combination therapies involving PI3K/AKT/mTOR inhibitors with other targeted agents or immunotherapies to enhance efficacy.

Need to understand better the molecular determinants of response to guide personalized treatment approaches. Trials exploring dual inhibition (e.g., sapanisertib) and combinations with other modalities.

[15,16,17,18]

RAF/MEK/ERK pathway inhibitors

Target MAPK pathway mutations, particularly BRAF-V600E, involved in tumor growth.

BRAF inhibitor dabrafenib effective in gliomas with BRAF-V600E mutation; combination with MEK inhibitor trametinib being tested to enhance efficacy and reduce resistance.

Challenges with blood-brain barrier penetration, potential for drug resistance, and side effects such as skin toxicity.

Investigating drug combinations to delay resistance development, particularly using MEK inhibitors alongside BRAF inhibitors.

Research into overcoming blood-brain barrier challenges and minimizing side effects while maintaining efficacy.

[19,20,21,22,23,24]

IDH Gene mutation inhibitors

Inhibit mutant IDH1/2 enzymes, which reprogram tumor metabolism and contribute to glioma growth.

IDH inhibitors (e.g., ivosidenib, vorasidenib) showing promise in low-grade gliomas (LGGs) with IDH mutations; ongoing trials to assess dosing and effectiveness in high-grade gliomas (HGGs).

Limited effectiveness in HGGs, need for further research on optimal dosing and combination therapies to improve outcomes.

Ongoing trials to refine dosing and evaluate the combination of IDH inhibitors with other targeted therapies or standard treatments like temozolomide.

Continued exploration of combination strategies and biomarker development to identify patients most likely to benefit. Focus on expanding efficacy beyond low-grade gliomas to more aggressive types.

[19, 24]

Immune checkpoint inhibitors

Block immune evasion mechanisms, such as PD-1/PD-L1 pathways, to enhance T-cell-mediated tumor destruction.

CAR-T cell therapies have shown potential in glioblastoma, extending survival in some patients; however, no phase III results yet.

High recurrence rates, incomplete understanding of optimal targets and delivery mechanisms, and limited penetration into tumor sites.

Optimizing CAR-T cell design and identifying novel immune checkpoint targets to improve efficacy and safety.

Further clinical trials to establish the safety and efficacy of CAR-T cells in larger, more diverse patient populations. Research into enhancing CAR-T cell penetration and retention in brain tumors.

[25,26,27]

TGF-β receptor inhibitors

Inhibit TGF-β, a key regulator that suppresses T-cell function within the tumor microenvironment and contributes to therapeutic resistance.

Galunisertib, a TGF-β receptor kinase inhibitor, was not effective in glioblastoma in trials; potential in combination with temozolomide to overcome resistance and improve outcomes.

Limited efficacy as monotherapy, need for combination approaches to enhance therapeutic response and overcome drug resistance.

Investigating combination therapies with TGF-β inhibitors and other standard treatments like temozolomide to address resistance mechanisms.

Future studies to explore biomarkers for TGF-β inhibitor response and to identify patient subsets that may benefit most. Trials combining TGF-β inhibitors with immune modulators or chemotherapy agents.

[28,29,30]

Cytokine therapy

Utilize cytokines like ILs and IFNs to boost immune responses or alter tumor microenvironment to suppress tumor growth.

IL-2, IL-4 gene vaccine, and IFN-α demonstrated positive responses in early trials; however, IFN-γ did not show significant benefits in combination with standard therapy for glioblastoma.

Variable efficacy depending on cytokine type, potential for significant side effects, and need for further trials to determine optimal combinations and dosing.

Developing cytokine-based combination therapies to synergize with existing standard of care or novel targeted therapies.

Continued investigation into the specific cytokine pathways involved in glioma immune modulation. Exploration of gene editing technologies to enhance cytokine-based therapies.

[31,32,33,34,35,36]