Jang, Mi-Hyeon

Abstract Cisplatin chemotherapy, although efficacious in resolution of cancer, potentiates cognitive impairments (known as chemobrain) affecting approximately 14 million cancer survivors in the United States. Cisplatin is a frontline chemotherapy used to treat ovarian, testicular, breast and brain cancers. Despite the high prevalence of clinical reports of cognitive impairments during and following chemotherapy, there is little information on how learning/memory are detrimentally affected and no known cure. To elucidate the mechanisms by which chemobrain impairs cognition, we implemented a mouse model resembling intermittent cisplatin chemotherapy in humans. Our preliminary studies revealed that repeated intermittent cisplatin treatment detrimentally affects the structure of neuronal brain cells in the hippocampus, a brain region known for its ability to control learning/memory, emotional behaviors and motor function. Although the molecular pathways vulnerable to cisplatin in the brain remain elusive, gene sequencing from the hippocampus of mice administered cisplatin identified the adenosine A2A receptor (Adora2a) protein was concentrated in elevated quantities in this brain region. Importantly, the Adora2a receptor protein is known for its critical role in learning/memory and has been found to play a role in neurodegenerative conditions. To investigate Adora2a functionality in cisplatin-induced chemobrain, we assessed the efficacy of the non-selective Adora2a antagonist caffeine, in preventing cisplatin-induced cognitive dysfunction. Caffeine was selected as a therapeutic due to its safe pharmacological profile, its universal availability, and low cost. Our translational approach employing the non-selective Adora2a antagonist caffeine, protected against cisplatin-induced body weight deficits and motor dysfunction, both of which are common clinical symptoms of chemotherapy. Interestingly, relative to cisplatin alone, mice treated with caffeine in combination with cisplatin exhibited improved dendritic spine densities in the hippocampus, suggesting improved neuronal morphology by caffeine. Given that Adora2a antagonists are known to enhance anti-tumor activity while also showing neuroprotective promise in neurodegenerative conditions, inhibiting Adora2a during cancer treatment may have far-reaching synergistic effects on quality of life improvement for cancer survivors. Citation Format: Alfredo Oliveros, Ana M. Corujo-Ramirez, Ki-Hyun Yoo, Jason Tang, Danielle Brogren, Mohammad A. Rashid, Yuanhang Liu, Mi-Hyeon Jang. Adora2a inhibition via caffeine as a novel therapeutic target for cisplatin-induced chemobrain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3115.

Abstract Cisplatin chemotherapy, although efficacious in positive resolution of cancer, adversely potentiates off-target cognitive dysfunction and affects approximately 14 million cancer survivors in the United States alone. Despite the high prevalence of chemotherapy induced cognitive impairments (known as chemobrain), there is little information on how memory and learning are impaired and no known cure. To elucidate the mechanisms by which chemobrain impairs cognition, we implement a novel experimental mouse model resembling clinical cisplatin-chemotherapy. Our results reveal that repeated cisplatin administration impairs hippocampal neuronal functional morphology, while inducing significant emotional and memory deficits. Although the molecular targets and pathways vulnerable to cisplatin in the central nervous system (CNS) are currently unknown, RNA-sequencing derived from mice administered cisplatin or vehicle revealed the G-protein coupled adenosine A2A receptor (Adora2a) known to be critical for synaptic plasticity and memory, as a promising therapeutic target for chemobrain. Bioinformatic analysis and qRT-PCR validation revealed significant induction of Adora2a mRNA expression by cisplatin in the adult hippocampus, a brain structure critical for learning and memory. Interestingly, while Adora2a is known to be expressed by neurons, astrocytes and other brain glia, confocal microscopy demonstrates that cisplatin specifically increases Adora2a expression in hippocampal neurons without affecting astrocytes, indicating that Adora2a expressing neurons are particularly vulnerable. To mechanistically determine whether elevated neuronal Adora2a functionality are implicated in cisplatin-induced chemobrain, we assessed the efficacy of Istradefylline (KW-6002), a selective Adora2a inhibitor, in preventing cisplatin-induced chemobrain. Our results indicate that selective pharmacological inhibition of Adora2a prevented cisplatin induced anxiety and cognitive impairments in the elevated plus maze, the Morris water maze and novel object recognition test. In addition, our translational approach employing the non-specific Adora2a antagonist caffeine, protected against cisplatin-induced impairments in body weight, motor learning and motor function. Therefore, our results suggest a critical regulatory role for Adora2a in cisplatin-induced cognitive and motor dysfunction. Given that Adora2a antagonists are proven to be safe and neuroprotective in neurodegeneration as well as in enhancing anti-tumor activity, inhibiting Adora2a may have far-reaching synergistic effects on cancer treatment and chemobrain. This work was supported by Mayo Clinic Breast SPORE (R50CA116201) and Regenerative Medicine Minnesota (RMM 091718 DS 005) to M.H.J. and the Bosarge Family Foundation-Waun Ki Hong Scholar Award to A.O. Citation Format: Alfredo Oliveros, Ki-Hyun Yoo, jun Tang, Ana M. Corujo, Danielle Brogren, Yuanhang Liu, Mi-Hyeon Jang. Adora2a inhibition as a novel therapeutic target for cisplatin chemobrain-induced cognitive dysfunction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4141.