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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
Targeting Metabolic Vulnerabilities in Glioblastoma: a Framework for Multi-node Combination Therapy
Vishal Gokani1, Anuhya Kotta1, Venkata Repaka2
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Purpose Of Review:
While glioblastoma (GBM) exhibits a poor prognosis despite standard therapy, targeted metabolic therapy is promising as adjuvant therapy. The purpose of this review is to delineate the rationale behind metabolic therapy, the bypass mechanisms conferring resistance to each therapy, and potential synergistic combination strategies.
Recent Findings:
Critical enzymes in glycolysis, glutaminolysis, lipid metabolism, nucleotide synthesis, and mitochondrial metabolism are promising individual targets of metabolic therapy and lead to cell death in preclinical studies. However, with metabolic monotherapy, GBM cells can rely on other isoforms or switch to alternative pathways for energy production and biosynthesis. Preclinical studies show that targeting multiple metabolic nodes with combination therapy blocks these resistance pathways and synergistically inhibits tumor growth. While metabolic monotherapies exhibit limited success, synergistic combination therapies may bypass resistance mechanisms and are more promising. Combination therapies delivered with standard of care may improve patient outcomes, and larger clinical trials are needed to establish the use of combination regimens to improve overall survival.
Insights
Targeting cancer cell metabolism offers a promising adjuvant therapy for glioblastoma (GBM). Combination metabolic therapies show synergistic effects by overcoming resistance mechanisms, suggesting improved patient outcomes with further clinical trials.
Area of Science:
- Oncology
- Metabolic Pathways
- Cancer Therapeutics
Background:
- Glioblastoma (GBM) presents a poor prognosis with standard treatments.
- Targeted metabolic therapy is being explored as an adjuvant treatment for GBM.
Purpose of the Study:
- To review the rationale for metabolic therapy in GBM.
- To identify resistance mechanisms to metabolic therapies.
- To explore synergistic combination strategies for metabolic therapy in GBM.
Main Methods:
- Literature review of preclinical and clinical studies on metabolic therapy in GBM.
- Analysis of metabolic pathways critical for GBM cell survival and proliferation.
- Evaluation of resistance mechanisms and combination strategies.
Main Results:
- Individual targeting of metabolic enzymes (glycolysis, glutaminolysis, lipid metabolism, etc.) shows promise in preclinical studies.
- GBM cells develop resistance to monotherapy by utilizing alternative metabolic pathways.
- Combination metabolic therapies targeting multiple nodes synergistically inhibit tumor growth and bypass resistance.
Conclusions:
- Metabolic monotherapy has limited success in GBM due to resistance.
- Synergistic combination metabolic therapies are more promising for overcoming resistance.
- Combination regimens delivered with standard care may improve patient outcomes, warranting larger clinical trials.
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