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Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Epidermal growth factor receptor: a re-emerging target in glioblastoma
Monika E Hegi1, Premnath Rajakannu, Michael Weller
1Laboratory of Brain Tumor Biology and Genetics, Service of Neurosurgery, Department of Clinical Neurosciences, University Hospital Lausanne, Switzerland. Monika.Hegi@chuv.ch
Purpose Of Review:
Amplification and overexpression of the epidermal growth factor receptor (EGFR) gene are a hallmark of primary glioblastoma (45%), making it a prime target for therapy. In addition, these amplifications are frequently associated with oncogenic mutations in the extracellular domain. However, efforts at targeting the EGFR tyrosine kinase using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for newly diagnosed or recurrent glioblastoma. Here, we review recent insights into molecular mechanisms relevant for effective targeting of the EGFR pathway.
Recent Findings:
Molecular workup of glioblastoma tissue of patients under treatment with small molecule inhibitors has established drug concentrations in the tumor tissue, and has shed light on the effectiveness of target inhibition and respective effects on pathway signaling. Further, functional analyses of interaction of small molecule inhibitors with distinct properties to bind to the active or inactive form of EGFR have provided new insights that will impact the choice of drugs. Finally, vaccination approaches targeting the EGFRvIII mutant featuring a tumor-specific antigen have shown promising results that warrant larger controlled clinical trials.
Summary:
A combination of preclinical and clinical studies at the molecular level has provided new insights that will allow refining strategies for targeting the EGFR pathway in glioblastoma.
Insights
Targeting the epidermal growth factor receptor (EGFR) in glioblastoma shows promise. New insights into molecular mechanisms and vaccination strategies may improve treatment efficacy for this brain cancer.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Epidermal growth factor receptor (EGFR) gene amplification and overexpression occur in 45% of primary glioblastomas.
- EGFR amplifications are often linked to oncogenic mutations in the extracellular domain.
- Previous attempts targeting EGFR tyrosine kinase with small molecules or antibodies yielded disappointing clinical efficacy in glioblastoma.
Purpose of the Study:
- To review recent molecular insights for effective targeting of the EGFR pathway in glioblastoma.
- To explore novel therapeutic strategies beyond traditional EGFR inhibition.
Main Methods:
- Review of preclinical and clinical studies.
- Analysis of molecular workup of glioblastoma tissue from patients treated with small molecule inhibitors.
- Functional analyses of small molecule inhibitor interactions with EGFR.
- Evaluation of vaccination approaches targeting EGFRvIII.
Main Results:
- Drug concentrations and target inhibition effectiveness were established in tumor tissues.
- Insights into small molecule inhibitor binding to active/inactive EGFR forms will influence drug selection.
- Vaccination strategies targeting the EGFRvIII mutant show promising results, warranting further clinical trials.
Conclusions:
- Molecular-level studies provide new insights for refining EGFR pathway targeting strategies in glioblastoma.
- A combination of preclinical and clinical findings will guide future therapeutic development.
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