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AMPA Receptor Modulation in the Treatment of High-Grade Glioma: Translating Good Science into Better Outcomes
1Stony Brook Medical Scientist Training Program, Renaissance School of Medicine at Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, USA.
Abstract:
Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15-20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain excitatory synaptic communication in the CNS. AMPA-glutamate receptor (AMPAR) signaling governs the majority of excitatory synaptic activity in the mammalian brain. AMPAR activation in glioma cells activates cellular pathways that enhance proliferation and invasion and confer resistance to approved GB therapeutics. In addition, this review places a specific emphasis on discussing the redefined GB cytoarchitecture that consists of neuron-to-glioma cell synapses, whose oncogenic activity is driven by AMPAR activation on glioma cells, and the discovery of tumor microtubes, which propagate calcium signals throughout the tumor network in order to enhance resistance to complete surgical resection and radiotherapy. These new discoveries notwithstanding, some evidence suggests that AMPAR activation can produce excitotoxicity in tumor cells. This disparity warrants a closer examination at how AMPAR modulation can be leveraged to produce more durable outcomes in the treatment of GB and tumors in peripheral organs that express AMPAR.
Insights
Glioblastoma (GB) treatment faces challenges due to neurotransmitter signaling. Targeting AMPA-glutamate receptors (AMPARs) in glioma cells may offer new therapeutic strategies for better patient outcomes.
Area of Science:
- Neuroscience
- Oncology
- Molecular Biology
Background:
- Glioblastoma (GB) treatment remains challenging, with limited median survival despite multimodal therapies.
- GB aggressiveness is linked to co-opted neurotransmitter signaling, particularly AMPA-glutamate receptor (AMPAR) pathways.
- AMPAR signaling in glioma cells promotes proliferation, invasion, and therapeutic resistance.
Purpose of the Study:
- To review the role of AMPA-glutamate receptor (AMPAR) signaling in glioblastoma (GB) aggressiveness.
- To discuss the implications of neuron-to-glioma cell synapses and tumor microtubes in GB.
- To explore the potential of AMPAR modulation as a therapeutic strategy for GB.
Main Methods:
- Literature review focusing on AMPAR signaling in glioblastoma.
- Analysis of recent discoveries in GB cytoarchitecture, including neuron-to-glioma synapses and tumor microtubes.
- Examination of evidence regarding AMPAR activation's dual role (oncogenic and excitotoxic) in tumor cells.
Main Results:
- AMPAR activation in glioma cells enhances proliferation, invasion, and resistance to standard GB treatments.
- Neuron-to-glioma cell synapses and tumor microtubes, driven by AMPAR signaling, contribute to GB aggressiveness and treatment resistance.
- AMPAR activation may also induce excitotoxicity in tumor cells, presenting a complex therapeutic target.
Conclusions:
- Understanding AMPAR signaling in GB is crucial for developing novel therapeutic approaches.
- Targeting AMPARs offers a potential strategy to overcome treatment resistance and improve outcomes in glioblastoma.
- Further research is warranted to elucidate the precise mechanisms of AMPAR modulation for durable GB treatment and other AMPAR-expressing tumors.
