Grant: Project Grant

Our prior work identified the membrane-bound adenosine-producing enzyme CD73 as a cancer target, spearheading the development of a new class of anti-cancer drugs targeting adenosine-producing enzymes and downstream adenosine receptors. Extracellular adenosine is mainly produced from extracellular ATP from the activity of CD39 and CD73. Adenosine suppresses immune cells through activation of the high-affinity adenosine A2A receptor. Several selective inhibitors of CD39, CD73 or A2A are now in clinical trials in cancer patients. Notably, early clinical data from Phase 1 studies suggest that patients with pancreatic cancer can benefit from CD73 or A2A-targeting agents. This is particularly encouraging given that pancreatic cancer is very lethal and generally resistant to other forms of immunotherapy, such as PD-1 inhibitors. Yet, how adenosine-generating CD39 and CD73 regulate the tumor microenvironment of pancreatic cancers remains largely unknown. Pancreatic cancer have some of the highest expression levels of CD73 and CD39. This project, which is in continuity with our already impactful research, will define the role of the adenosine pathway in pancreatic cancer. It will also clarify the mechanism of anti-CD73 versus anti-CD39 therapy, and shed new lights on potential liabilities of targeting A2A with regards to liver cancer. Altogether, this project will have an important impact on the design of therapies targeting the adenosine pathway.