Protein Kinase Inhibitor for Glioblastoma

• Comparative analysis of the antiglioblastoma activity of adenosine A_2A receptor and CK1δ blockers
• BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAF^V600E-mutant glioma
• Unravelling the link between circadian clock genes and brain tumors: From pathological disruptions to potential therapeutic interventions
• Natural Product Daidzin Inhibits Glioma Development via Suppressing the LRP5-Mediated GSK-3β/c-Myc Signaling Pathway
• Multiprotein Silencing Using WRAP-Based Nanoparticles: A Proof of Concept
• Drug Combinations Targeting FAK and MEK Overcomes Tumor Heterogeneity in Glioblastoma
• Autophagy-mediated downregulation of AXL and TIM-1 promotes sustained Zika virus infection
• TMBIM1 promotes epithelial mesenchymal transition by accelerating autophagic degradation of E-cadherin in glioblastoma

Protein kinases regulate signaling pathways for glioblastoma proliferation, survival, and angiogenesis. Inhibiting specific kinases offers a targeted approach to disrupt these oncogenic mechanisms.

• EGFR (Epidermal Growth Factor Receptor)
  1. Mutated or amplified in ~40-60% of GBMs
  2. Targeted by: Erlotinib, Gefitinib, Osimertinib (3rd gen)
  3. Challenges: Limited BBB penetration, intratumoral heterogeneity

• PDGFR (Platelet-Derived Growth Factor Receptor)
  1. Overexpressed in a subset of GBMs
  2. Targeted by: Imatinib, Sunitinib
  3. Clinical results have been disappointing

• VEGFR (Vascular Endothelial Growth Factor Receptor)
  1. Crucial for GBM angiogenesis
  2. Targeted by: Cediranib, Regorafenib
  3. Regorafenib has shown modest survival benefit (REGOMA trial)

• mTOR (mammalian Target of Rapamycin)
  1. Downstream effector in PI3K/AKT pathway
  2. Targeted by: Everolimus, Temsirolimus
  3. Mixed results; resistance and feedback loops limit efficacy

• PI3K/AKT Pathway
  1. Frequently activated in GBM
  2. Targeted by: Buparlisib (PI3K inhibitor), Perifosine (AKT inhibitor)
  3. Limited clinical benefit observed

• SRC Family Kinases
  1. Promote invasion and resistance
  2. Targeted by: Dasatinib
  3. Limited efficacy as monotherapy

• Regorafenib
  1. Inhibits VEGFR, PDGFR, FGFR, RAF
  2. Demonstrated OS benefit in recurrent GBM (REGOMA trial)
  3. Side effects: fatigue, hypertension, hand-foot syndrome

• Pazopanib, Sorafenib, Lenvatinib
  1. Broad-spectrum tyrosine kinase inhibitors under investigation

• Blood-Brain Barrier (BBB): Poor drug penetration
• Tumor heterogeneity: Genomic variability limits targetable subsets
• Adaptive resistance mechanisms: Feedback activation of bypass pathways
• Limited monotherapy efficacy: Combination strategies being explored

• Combination with radiotherapy or immune checkpoint inhibitors
• Nanoparticle delivery of kinase inhibitors to cross BBB
• Personalized therapy based on molecular profiling (e.g., EGFRvIII status)

A Meta-analysis, based on searches in PubMed and Web of Science, evaluated 12 randomized controlled trials (RCTs) examining PKIs in patients with newly diagnosed or recurrent GBM. Pooled analysis of shared clinical outcomes - progression-free survival (PFS) and overall survival (OS) - revealed a lack of significant improvements with the use of PKIs. In newly diagnosed GBM, no significant differences were observed in median [-1.02 months, 95 % confidence interval (CI), -2.37-0.32, p = 0.14] and pooled [hazard ratio (HR) = 1.13, 95 % CI, 0.95-1.35, p = 0.17) OS, or in median (0.34 months, 95 % CI, -0.9-1.58, p = 0.60) and pooled (HR = 0.98, 95 % CI, 0.76-1.27, p = 0.89) PFS, when comparing PKI addition to standard chemo-radiotherapy versus chemo-radiotherapy alone. In recurrent GBM, three different analyses were conducted: PKI versus other treatments, PKI combined with other treatments versus those treatments alone, PKI versus PKI combined with other treatments. Also, across these analyses, no significant clinical benefits were found. For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95 % CI, -2.12-0.55, p = 0.25; -0.23 months, 95 % CI, -0.79-0.34, p = 0.43, respectively), and similar non-significant results were observed in the pooled analyses (OS: HR = 0.89, 95 % CI, 0.59-1.32, p = 0.55; PFS: HR = 0.83, 95 % CI, 0.63-1.11, p = 0.21). Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development ¹⁾.

This meta-analysis provides a sobering but necessary evaluation of PKIs in GBM, emphasizing their limited impact on survival in current clinical practice. The findings underscore the need for precision oncology approaches and more biologically rational trial designs, rather than broad application of PKIs across all GBM patients.