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Cut the fat: targeting cholesterol and lipid metabolism in glioblastoma
Safet Zekanovic1, Puspha Achaiber Sing1, Sieger Leenstra1
1Department of Neurosurgery, Brain Tumor Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
Abstract:
In the past decades, much research has been focused on identifying oncogenic signaling events in glioblastoma (GBM). Based on these findings, novel therapeutics have been extensively tested in clinical trials. These include targeted agents (e.g., kinase inhibitors), anti-angiogenic drugs, and immunotherapies. Unfortunately, no survival benefit has been demonstrated with the use of these agents. The lack of efficacy observed in the past decades poses the question of whether we are targeting the right pathways to halt the growth of GBM. In this review article, we discuss the intricacies of cholesterol and lipid metabolism in GBM. We provide an overview of which oncogenic signaling pathways are fueled by the aberrant cholesterol and lipid metabolism in GBM. Importantly, we also discuss how metabolic rewiring in the context of cholesterol and lipids can contribute to immune evasion in GBM. Lastly, we provide an overview of current drugs targeting cholesterol and fatty acid metabolism and their potential to serve as targeted therapies for GBM.
Insights
Glioblastoma (GBM) treatments targeting signaling pathways have failed. This review explores how cholesterol and lipid metabolism fuel GBM, contributing to immune evasion and offering potential new therapeutic targets.
Area of Science:
- Oncology
- Metabolic pathways
- Neuroscience
Background:
- Glioblastoma (GBM) research has focused on oncogenic signaling pathways.
- Novel therapeutics like kinase inhibitors, anti-angiogenic drugs, and immunotherapies have shown no survival benefit in GBM clinical trials.
- This lack of efficacy questions the current therapeutic targets for GBM.
Purpose of the Study:
- To review the role of cholesterol and lipid metabolism in GBM.
- To identify oncogenic signaling pathways fueled by aberrant lipid metabolism in GBM.
- To discuss how metabolic rewiring contributes to immune evasion in GBM and explore potential therapeutic strategies.
Main Methods:
- Literature review of studies on glioblastoma, cholesterol metabolism, lipid metabolism, and cancer signaling pathways.
- Analysis of how metabolic alterations in GBM influence oncogenic signaling and immune evasion.
- Overview of current drugs targeting lipid metabolism for potential GBM therapy.
Main Results:
- Aberrant cholesterol and lipid metabolism are intricately linked to GBM growth and progression.
- Metabolic rewiring, particularly involving lipids, contributes significantly to immune evasion in the GBM microenvironment.
- Targeting cholesterol and fatty acid metabolism presents a promising avenue for novel GBM therapies.
Conclusions:
- Current therapeutic strategies for GBM targeting oncogenic signaling have been largely ineffective.
- Cholesterol and lipid metabolism represent critical, yet under-explored, drivers of GBM.
- Targeting metabolic pathways involved in lipid processing offers a potential new strategy to improve GBM treatment outcomes.
