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EGFR, the Lazarus target for precision oncology in glioblastoma
Benjamin Lin1, Julia Ziebro1, Erin Smithberger1,2
1Department of Pathology, Division of Neuropathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract:
The Lazarus effect is a rare condition that happens when someone seemingly dead shows signs of life. The epidermal growth factor receptor (EGFR) represents a target in the fatal neoplasm glioblastoma (GBM) that through a series of negative clinical trials has prompted a vocal subset of the neuro-oncology community to declare this target dead. However, an argument can be made that the core tenets of precision oncology were overlooked in the initial clinical enthusiasm over EGFR as a therapeutic target in GBM. Namely, the wrong drugs were tested on the wrong patients at the wrong time. Furthermore, new insights into the biology of EGFR in GBM vis-à-vis other EGFR-driven neoplasms, such as non-small cell lung cancer, and development of novel GBM-specific EGFR therapeutics resurrects this target for future studies. Here, we will examine the distinct EGFR biology in GBM, how it exacerbates the challenge of treating a CNS neoplasm, how these unique challenges have influenced past and present EGFR-targeted therapeutic design and clinical trials, and what adjustments are needed to therapeutically exploit EGFR in this devastating disease.
Insights
The Lazarus effect in glioblastoma (GBM) research shows that targeting the epidermal growth factor receptor (EGFR) may be viable. Past trials failed due to incorrect patient selection and drug timing, not a flawed target.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Precision Medicine
Background:
- The epidermal growth factor receptor (EGFR) is a target in glioblastoma (GBM), a fatal brain cancer.
- Previous clinical trials targeting EGFR in GBM have largely failed, leading some to consider the target 'dead'.
- Precision oncology principles may have been overlooked in earlier EGFR-targeted GBM trials.
Purpose of the Study:
- To re-evaluate the epidermal growth factor receptor (EGFR) as a viable therapeutic target in glioblastoma (GBM).
- To examine the unique biology of EGFR in GBM and its implications for central nervous system (CNS) tumor treatment.
- To analyze past and present EGFR-targeted therapeutic designs and clinical trials in GBM.
Main Methods:
- Review of distinct EGFR biology in GBM compared to other cancers.
- Analysis of challenges in treating CNS neoplasms with EGFR-targeted therapies.
- Examination of clinical trial designs and outcomes for EGFR-targeted drugs in GBM.
Main Results:
- Initial EGFR-targeted therapies in GBM may have failed due to incorrect drug selection, patient stratification, and treatment timing.
- New understanding of GBM-specific EGFR biology and novel therapeutics offer renewed potential.
- EGFR biology in GBM presents unique challenges for therapeutic development in CNS neoplasms.
Conclusions:
- The epidermal growth factor receptor (EGFR) target in glioblastoma (GBM) is not inherently dead but requires a refined therapeutic strategy.
- Future success hinges on understanding GBM's unique EGFR biology and implementing precision oncology principles.
- Novel GBM-specific EGFR therapeutics and adjusted clinical trial designs are crucial for future research.
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