Targeting A3 and A2A adenosine receptors in the fight against cancer

ABSTRACT

Introduction: There is a vicious cycle of tumor hypoxia, high adenosine levels, immune suppression and cancer growth that involves the use of adenosine receptor ligands in tumors. After several years of research, the candidates emerging as promising new anticancer drugs are A₃ adenosine receptor agonists and A_2A receptor antagonists.

Areas covered: The authors give an updated overview of the field related to A₃ receptor agonists and A_2A receptor antagonists in cancer and propose their perspectives on the status of these compounds in oncology. The rationale for the modulation of adenosine receptors in cancer is addressed, starting from the first in vitro evidence of their efficacy up to the animal and clinical studies.

Expert opinion: A₃ and A_2A receptors are attractive targets in oncologic therapy due to their involvement in cancer progression and immune-resistance. Of relevance, the A₃ subtype is also a tumor marker to be used in a personalized drug treatment program while the A_2A receptor, playing a non-redundant role in immunomodulation, may be blocked in combination with checkpoint inhibitors to improve their efficacy. The future will reveal how successful this approach is in the fight against cancer.

KEYWORDS:

• Adenosine receptors
• cancer
• cell proliferation
• immunoescaping
• immunoprotection
• clinical trials

Article Highlights

• Adenosine is an endogenous and ubiquitous nucleoside, deriving from dephosphorylation of both intracellular and extracellular ATP, rising under stressed conditions present in several pathologies and acting through interaction with four GPCR receptors, named A₁, A_2A, A_2B, and A₃.

• Adenosine plays a crucial role in the regulation of cancer cell biology by regulating tumor and immune cells through interaction with its cognate A₃ and A_2A receptors. A vicious cycle of tumor hypoxia, increased adenosine concentrations, immune suppression, and cancer growth implies the use of adenosine receptor ligands in tumors.

• Highly selective A₃ agonists with potential as anticancer drugs have been developed, exploiting their anti-proliferative and proapoptotic effects. These ligands represent a new and original anticancer approach, addressing for the first time both cancer and healthy immune cells.

• A₃ receptors are overexpressed in almost all cancer types, indicating that A₃ agonists could offer the opportunity of an innovative personalized cancer therapy. The A₃ receptor represents an effective tumor biomarker, being its overexpression at baseline in correlation with a positive response in patients.

• Potent and selective A_2A receptor antagonists have been developed based on the awareness that hypoxic generation of adenosine in tumors is crucial for their immuno-escape A_2A receptors-mediated. Based on the ability of these compounds to activate the immune system, clinical trials have been designed to evaluate their antitumor efficacy in combination with immunological drugs.

• The A₃ agonist Namodenoson, as well as A_2A antagonists Preladenant, PBF-509, CPI-444, and AZD4635, in clinical development, demonstrate a good safety profile, no side effects, and an acceptable pharmacokinetic behavior, thereby giving hope for the future for a new generation of drugs capable of changing the fate of numerous types of tumor.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.