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Published on: February 17, 2023
Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance
1Department of Neurology, University of California, San Francisco, CA 94158-9001, USA.
Abstract:
Gliomas represent the most common primary brain tumor and among the most aggressive of cancers. Patients with glioma typically relapse within a year of initial diagnosis. Recurrent glioma is associated with acquired therapeutic resistance. Although neurosurgical resection, radiation and chemotherapy provide clear benefit, survival remains disappointing. It is, therefore, critical that we identify effective medical therapies and appropriate tumor biomarkers in patients at initial presentation, to promote durable responses in glioma. Pathways linking receptor tyrosine kinases, PI3 kinase, Akt, and mTOR feature prominently in this disease and represent therapeutic targets. Small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity. Disappointingly, however, preclinical studies demonstrate these agents to be primarily cytostatic rather than cytotoxic to glioma cells. Here, we detail activation of the EGFR-PI3K-Akt-mTOR signaling network in glioma, review class I PI3K inhibitors, discuss roles for Akt, PKC and mTOR, and the importance of biomarkers. We further delineate attempts to target both single and multiple components within the EGFR-PI3K-Akt-mTOR axes. Lastly, we discuss the need to combine targeted therapies with cytotoxic chemotherapy, radiation and with inhibitors of survival signaling to improve outcomes in glioma.
Insights
Glioma, a common brain cancer, often recurs due to resistance. Targeting the EGFR-PI3K-Akt-mTOR pathway shows promise, but combination therapies are needed for better patient outcomes.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Medicine
Background:
- Gliomas are aggressive primary brain tumors with poor survival rates.
- Recurrent gliomas exhibit therapeutic resistance, necessitating novel treatment strategies.
- The EGFR-PI3K-Akt-mTOR signaling network is frequently dysregulated in glioma.
Purpose of the Study:
- To review the activation of the EGFR-PI3K-Akt-mTOR pathway in glioma.
- To discuss current and potential therapeutic strategies targeting this network.
- To emphasize the importance of biomarkers and combination therapies for improved glioma treatment.
Main Methods:
- Review of preclinical and clinical studies on glioma.
- Analysis of signaling pathways, including receptor tyrosine kinases, PI3K, Akt, and mTOR.
- Evaluation of targeted therapies, chemotherapy, and radiation in glioma treatment.
Main Results:
- The EGFR-PI3K-Akt-mTOR pathway is a key driver in glioma.
- Current targeted therapies (e.g., PI3K inhibitors) show limited efficacy as single agents, often being cytostatic.
- Biomarkers are crucial for identifying patients who may benefit from targeted therapies.
Conclusions:
- Targeting the EGFR-PI3K-Akt-mTOR axis is a rational approach for glioma therapy.
- Combination strategies involving targeted agents, chemotherapy, and radiation are essential for overcoming resistance and improving outcomes.
- Further research into biomarkers and combination therapies is critical for durable responses in glioma patients.
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