The recent FDA approval of the prostate cancer vaccine Provenge® and the monoclonal antibody Yervoy® (anti melanoma), are milestones in cancer immunotherapy. Despite this excitement there exists a critical need to broaden our knowledge of underlying tumor protection mechanisms. In this presentation, I will discuss a novel immunosuppressive pathway, wherein hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2A receptors on the surface of active immune cells. Extensive studies have revealed that antagonism of A2A receptors on immune cells have led to a total tumor rejection in mice. In unrelated applications, selective and long-lived A2AR antagonists have been developed as agents for Parkinson’s disease. Our laboratories have successfully synthesized a functional library of A2A antagonists, including KW6002, KW-octaethylene glycol monomethyl ether (KW-PEG), Tozadenant and PEG-ylated versions of Preladenant, which have shown promising preliminary data in mouse models. Future plans include synthesis and scale up of derivatives using novel coupling chemistry, preparation of PET probes, and exploring mechanism of action through assay guided Quantitative Structure–Activity Relationship (QSAR).

Targeting the hypoxia-adenosinergic pathway via A2AR antagonists; Toward cancer immunotherapeutics

249th National Meeting (2015)

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