Protein Kinase Inhibitor for Glioblastoma [Neurosurgery Wiki]

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====== Protein Kinase Inhibitor for Glioblastoma ======

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/10QQLaXyfCAHaHFIPcNlHKnZSE35ydmhMRPAjkuJvP98C99QQa/?limit=15&utm_campaign=pubmed-2&fc=20250519021301}}

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

===== Key Kinase Targets =====
  * **[[EGFR]] (Epidermal Growth Factor Receptor)**  
    - Mutated or amplified in ~40-60% of GBMs  
    - Targeted by: Erlotinib, Gefitinib, Osimertinib (3rd gen)
    - Challenges: Limited BBB penetration, intratumoral heterogeneity

  * **[[PDGFR]] (Platelet-Derived Growth Factor Receptor)**  
    - Overexpressed in a subset of GBMs  
    - Targeted by: Imatinib, Sunitinib  
    - Clinical results have been disappointing

  * **[[VEGFR]] (Vascular Endothelial Growth Factor Receptor)**  
    - Crucial for GBM angiogenesis  
    - Targeted by: Cediranib, Regorafenib  
    - Regorafenib has shown modest survival benefit (REGOMA trial)

  * **[[mTOR]] (mammalian Target of Rapamycin)**  
    - Downstream effector in PI3K/AKT pathway  
    - Targeted by: Everolimus, Temsirolimus  
    - Mixed results; resistance and feedback loops limit efficacy

  * **[[PI3K]]/[[AKT]] Pathway**  
    - Frequently activated in GBM  
    - Targeted by: Buparlisib (PI3K inhibitor), Perifosine (AKT inhibitor)  
    - Limited clinical benefit observed

  * **SRC Family Kinases**  
    - Promote invasion and resistance  
    - Targeted by: Dasatinib  
    - Limited efficacy as monotherapy

===== Multi-Kinase Inhibitors =====
  * **[[Regorafenib]]**  
    - Inhibits VEGFR, PDGFR, FGFR, RAF  
    - Demonstrated OS benefit in recurrent GBM (REGOMA trial)  
    - Side effects: fatigue, hypertension, hand-foot syndrome

  * **[[Pazopanib]], [[Sorafenib]], [[Lenvatinib]]**  
    - Broad-spectrum tyrosine kinase inhibitors under investigation

===== Current Challenges =====
  * **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

===== Promising Directions =====
  * 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)

===== Meta-analysis =====

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
((Pinto-Fraga J, García-Chico C, Lista S, Lacal PM, Carpenzano G, Salvati M, Santos-Lozano A, Graziani G, Ceci C. Protein kinase inhibitors as targeted therapy for glioblastoma: a meta-analysis of randomized controlled clinical trials. Pharmacol Res. 2025 Feb;212:107528. doi: 10.1016/j.phrs.2024.107528. Epub 2025 Jan 8. Erratum in: Pharmacol Res. 2025 May 17:107784. doi: 10.1016/j.phrs.2025.107784. PMID: 39637954.)).
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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.