Adenosine Targeting as a New Strategy to Decrease Glioblastoma Aggressiveness

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.

Metabolic partitioning in the brain and its hijacking by glioblastoma

“…Preclinical studies also support the continued investigation of adenosine signaling blockade in GBM therapy ( Jin et al 2021 ; Bova et al 2022 ). Inhibition of the adenosine receptor A 2B R, which is highly up-regulated on GBM cells ( Fig.…”

Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy

“…Additionally, adenosine can stimulate the accumulation of MDSCs within TME and promote MDSCs expansion ( 172 ). Moreover, activation of A2AR on neutrophils, M1 macrophages, NK cells, Th1 cells and DCs inhibited antitumor cytokines and chemokines production ( 173 ). Finally, the adenosine stimulated cancer cells result in enhanced proliferation, migration and metastasis in enhanced proliferation, migration and metastasis ( 174 ).…”

PET Agents for Primary Brain Tumor Imaging

“…Adenosine and its receptors have multiple roles in the brain, including activation of microglia/macrophages and neurons, regulation of the immune response, and modulation of neurotransmitter release and neuronal plasticity. In brain tumors, increased levels of adenosinecreated by the tumor microenvironment, e.g., hypoxiaare thought to inhibit T cells leading to immune response evasion; the effect of adenosine on tumor cell proliferation (through the MAPK signaling pathway) has been more controversial, with equal reports on anti-tumor effects (140). 18 F-CPFPX is a specific ligand for the adenosine receptor A1AR (Figure 7) and in one preliminary study showed uptake restricted to the peritumoral tissue, suggesting a possible cellular reaction of this tissue to infiltrating tumor cells; however, T/N ratios were low and the at that time ambivalent role of adenosine receptors likely precluded further investigations (141).…”