PII-031 - REVIEW OF TRANSLATIONAL CANCER RESEARCH TARGETING ADENOSINE RECEPTOR A2AR.

J. Winfield, Y. Qin, M. Grigoruta; The University of Texas at El Paso, El Paso, Tx, United States.

Background: A2AR is a G-coupled protein receptor activated by extracellular adenosine. Adenosine-A2AR signaling pathway is associated with tumor progression and immune evasion. Adenosine is produced through dephosphorylation of extracellular ATP by ectonucleotidases CD39 and CD73. A2AR expressed on tumor cells is activated leading to a signal cascade of cAMP and PIK3/AKT. This cascade promotes anti-apoptosis, tumor growth, and metastasis. Inversely, A2AR activation suppresses the function of CD4+ and CD8+ T cells, NK cells, and macrophages while enhancing the effects of regulatory T cells (Tregs) and myeloid-derived suppressor cells. A2AR activation is sustained through high levels of adenosine production by upregulation of CD73 and CD39 in the tumor microenvironment (TME) due to a feedback loop involving hypoxia and induction by Tregs. The immunosuppressive effects of A2AR signaling hinder the effectiveness of cancer immunotherapies. This review aims to highlight the clinical progress of translational cancer research targeting A2AR.

Methods: Drug development progress on the current state of A2AR translational cancer research was collected from Clinicaltrial.gov, PubMed, Journal of Clinical Oncology, Journal of Clinical Pharmacology and Therapeutics, and AACR Journals. Keywords used were “A2Ar AND cancer”, “A2Ar AND cancer outcomes", and “A2Ar AND cancer prognosis”. Results were collected from papers and abstracts that included human subjects and drug treatment or A2AR-associated biomarkers.

Results: There are twenty-one clinical trials targeting A2AR in a variety of tumors. Renal cell carcinoma and non-small cell lung cancer are the most studied malignancies. Patient tumor genomics and The Cancer Genome Atlas reveal that A2AR expression is correlated with several biomarkers and poor patient prognosis. A2AR targeted monotherapy or in combination with chemotherapy, and other immunotherapies demonstrates enhanced immune surveillance, and PK/PD profiling demonstrates the safety, tolerability, and viability of these various drug combinations.

Conclusion: Adenosine Signaling and A2AR inhibition is a viable target and prognostic indicator for cancer outcome. These studies illustrate the complexity of adenosine signaling and provide potential strategies for increasing immunotherapeutic response.