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Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness
Valentina Bova1, Alessia Filippone1, Giovanna Casili1
1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31-98166 Messina, Italy.
Abstract:
Glioblastoma is the most commonly malignant and aggressive brain tumor, with a high mortality rate. The role of the purine nucleotide adenosine and its interaction with its four subtypes receptors coupled to the different G proteins, A1, A2A, A2B, and A3, and its different physiological functions in different systems and organs, depending on the active receptor subtype, has been studied for years. Recently, several works have defined extracellular adenosine as a tumoral protector because of its accumulation in the tumor microenvironment. Its presence is due to both the interaction with the A2A receptor subtype and the increase in CD39 and CD73 gene expression induced by the hypoxic state. This fact has fueled preclinical and clinical research into the development of efficacious molecules acting on the adenosine pathway and blocking its accumulation. Given the success of anti-cancer immunotherapy, the new strategy is to develop selective A2A receptor antagonists that could competitively inhibit binding to its endogenous ligand, making them reliable candidates for the therapeutic management of brain tumors. Here, we focused on the efficacy of adenosine receptor antagonists and their enhancement in anti-cancer immunotherapy.
Insights
Extracellular adenosine protects glioblastoma by accumulating in the tumor microenvironment. Adenosine A2A receptor antagonists show promise in enhancing anti-cancer immunotherapy for brain tumors.
Area of Science:
- Neuro-oncology
- Immunology
- Molecular Biology
Background:
- Glioblastoma is an aggressive brain tumor with a high mortality rate.
- Extracellular adenosine accumulates in the tumor microenvironment, acting as a tumor protector.
- This accumulation is linked to A2A receptor interaction and increased CD39/CD73 expression under hypoxia.
Purpose of the Study:
- To investigate the efficacy of adenosine receptor antagonists in glioblastoma treatment.
- To explore the potential of these antagonists in enhancing anti-cancer immunotherapy.
- To understand the role of adenosine pathway modulation in brain tumor therapy.
Main Methods:
- Review of preclinical and clinical research on adenosine pathway modulators.
- Focus on selective A2A receptor antagonists.
- Analysis of adenosine's interaction with its receptor subtypes (A1, A2A, A2B, A3).
Main Results:
- Extracellular adenosine accumulation promotes glioblastoma growth.
- Selective A2A receptor antagonists competitively inhibit adenosine binding.
- These antagonists are promising candidates for enhancing immunotherapy in brain tumors.
Conclusions:
- Adenosine receptor antagonists represent a viable therapeutic strategy for glioblastoma.
- Targeting the adenosine pathway can significantly enhance anti-cancer immunotherapy efficacy.
- Further research into adenosine antagonists is crucial for brain tumor treatment.
