Targeting Adenosine A2A Receptor as a Novel Regenerative Therapy in Improving Chemobrain

In the United States, cognitive dysfunction stemming from chemotherapy (chemobrain) is a major adverse condition affecting approximately 14 million cancer survivors with no known cure. Therefore, in this application, we aim to determine whether targeting the adenosine A2A receptor (Adora2a) is an effective regenerative strategy in promoting dendrite spine regeneration and improving chemotherapy-induced chemobrain. This understanding will provide insight into development of novel therapeutic interventions that prevent chemotherapy-induced cognitive dysfunction, thus resulting in a better quality of life for cancer survivors.

Research Focus: Cognitive dysfunction from chemotherapy

Year 1 Progress Report:

Chemotherapy-induced cognitive impairment (also known as chemobrain) adversely affects cancer survivors and has emerged as a significant medical problem. Unfortunately, there is no known cure and novel therapeutic approaches are urgently needed. Aided by Regenerative Medicine Minnesota, we identified the adenosine A_2A receptor (A_2AR) as the most profoundly up-regulated gene by cisplatin in adult mouse brain region critical for learning and memory. Importantly, these deficits are significantly recovered by istradefylline, a potent and selective A_2AR antagonist. Istradefylline has been recently approved by the FDA for Parkinson’s disease, and other A_2AR antagonists (e.g. ciforadenant) are undergoing clinical trials against various cancers. Therefore, istradefylline has emerged as a promising compound possessing far-reaching therapeutic effects that can be applied quickly and safely to clinical trials of chemobrain, ultimately improving quality of life for cancer survivors.