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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Small molecule tyrosine kinase inhibitors in glioblastoma
1College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon, 21936, South Korea.
Abstract:
Glioblastoma (GBM) is the most common malignant primary brain tumor, with poor survival despite treatment with surgery, radiotherapy, and chemotherapy with temozolomide. Little progress has been made over the last two decades, and there remain unmet medical needs. Approximately 45% of patients with GBM carry EGFR mutations, and 13% of them possess altered PDGFR genes. Moreover, VEGF/VEGFR mutations are also observed in the patient population. Tyrosine kinase inhibitors (TKIs) are emerging cancer therapy drugs that inhibit signal transduction cascades affecting cell proliferation, migration, and angiogenesis. Indications for small molecule TKIs have been successfully expanded to multiple types of cancer; however, none of the TKIs have been approved for patients with GBM. In this review, we summarize clinical trials of small molecule TKIs in patients with GBM and plausible hypotheses for negative clinical study results. We also discuss the potential TKI candidates that presented significant preclinical outcomes in patients with GBM.
Insights
Despite advances, glioblastoma (GBM) treatment remains challenging. This review examines tyrosine kinase inhibitors (TKIs) for GBM, exploring clinical trial outcomes and future therapeutic potential for this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Cancer Pharmacology
- Molecular Oncology
Background:
- Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with limited therapeutic progress and poor patient survival.
- EGFR, PDGFR, and VEGF/VEGFR mutations are present in a significant portion of GBM patients, representing potential therapeutic targets.
- Tyrosine kinase inhibitors (TKIs) show promise in cancer therapy by targeting signaling pathways crucial for tumor growth and angiogenesis.
Purpose of the Study:
- To review clinical trials of small molecule TKIs in glioblastoma patients.
- To explore hypotheses explaining the negative outcomes of TKI clinical studies in GBM.
- To identify potential TKI candidates with promising preclinical results for GBM treatment.
Main Methods:
- Systematic review of published clinical trials involving small molecule TKIs for glioblastoma.
- Analysis of preclinical data for TKI candidates demonstrating efficacy in GBM models.
- Literature review to identify common genetic alterations (EGFR, PDGFR, VEGF/VEGFR) in GBM.
Main Results:
- Despite preclinical promise, no small molecule TKIs have been approved for GBM treatment to date.
- Several clinical trials have yielded negative results, necessitating an investigation into underlying reasons.
- Certain TKI candidates have shown significant preclinical efficacy, suggesting potential for future development.
Conclusions:
- The clinical application of TKIs in glioblastoma faces significant hurdles, requiring further research into efficacy and patient selection.
- Understanding the molecular drivers and resistance mechanisms in GBM is crucial for successful TKI therapy.
- Future research should focus on novel TKI strategies and combination therapies to improve outcomes for glioblastoma patients.
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