Targeting the A2B Adenosine Receptor for Immunoprevention of Pancreatic Cancer

The adenosine signaling pathway has emerged as an important mediator of the tumor microenvironment. In this pathway, adenosine monophosphate (AMP) is converted to adenosine through CD73 activity, which is elevated in pancreatic intraepithelial neoplasia (PanIN), causing accumulation of adenosine in the precancerous microenvironment (1-6). Adenosine signals via adenosine receptors promoting immune suppression in the microenvironment (7-9). There are 4 adenosine receptors (A1A, A2A, A2B and A3AR) which can be co-expressed on stromal and epithelial cells (10). Among the adenosine receptors, the A2B receptor is the only one highly expressed in PanINs and PDAC and is also predictive of poor prognosis (11). These data suggest that the presence of the adenosine A2B receptor is clinically relevant. There are several ongoing efforts targeting the adenosine pathway therapeutically in PDAC patients. The overall goal of this project is to evaluate the pharmacokinetics and efficacy of A2B inhibitors in genetically engineered mouse (GEM) models (GEMMs) that recapitulate human PanIN initiation and progression to advanced PanIN. The data obtained from this project would be essential for the future development of a preventive clinical trial in a PDAC high risk population, such as the one followed at MD Anderson Cancer Center.