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A Novel Target to Mitigate Chemobrain

By Christina Leah B. Kline, PhD

Alfredo Oliveros, PhD

Chemotherapy-induced cognitive impairment, also known as chemobrain, can affect up to 75% of patients during treatment, and can plague a third of cancer survivors years after treatment (1). Unfortunately, no management strategies have been developed due to a lack of understanding of the pathophysiological mechanisms that drive chemobrain.

Alfredo Oliveros, PhD, currently a Research Associate at the Rutgers University Department of Neurosurgery, received The Bosarge Family Foundation-Waun Ki Hong Scholar Award for Regenerative Cancer Medicine in 2019 while a postdoctoral fellow at the Mayo Clinic. AACR grant funding supported his efforts to elucidate how chemotherapy detrimentally affects the regenerative neurobiology of cancer survivors to induce cognitive dysfunction.   

In a recent paper in the Proceedings of the National Academy of Sciences, Dr. Oliveros and his colleagues reported that cisplatin administration induced the upregulation of A2AR gene and protein expression in the mouse hippocampus, which is known for its ability to control memory function (2).  Treatment with an FDA-approved selective A2AR antagonist, KW-6002 (istradefylline), reversed cisplatin-induced body weight loss, providing the first clue to the protective benefits of A2AR inhibition by istradefylline.

Ingenuity Pathway Analysis of gene expression from RNA sequencing showed that increased A2AR expression in the hippocampus mapped to biological pathways associated with learning, memory, and cognition, as well as neuronal development, morphogenesis, and proliferation. Conducting memory and anxiety tests in their mouse models, the research group confirmed that KW-6002 prevented cisplatin-induced anxiety-like behavior and cisplatin-induced memory deficits.

This improvement in cognitive ability with A2AR antagonism may be explained at least in part by the effects of cisplatin and KW-6002 on neurogenesis. The research group had previously shown that cisplatin impaired adult hippocampal neurogenesis in the hippocampal dentate gyrus, leading to cognitive impairment (3). In this present work, they performed immunostaining of the immature neuron marker doublecortin (DCX+) and found that while cisplatin alone suppressed DCX+ expression, co-treatment with KW-6002 significantly prevented this decrease in DCX+ neurons in the hippocampal dentate gyrus. Similarly, while cisplatin treatment resulted in a decrease in total dendrite length, KW-6002 attenuated these reductions. Nevertheless, additional studies need to be conducted to investigate other mechanisms of cisplatin-induced cognitive impairment, such as synaptic plasticity (4), and assess whether A2AR antagonism can also mitigate these negative effects.

Dr. Oliveros and his mentor, Associate Professor Dr. Mi-hyeon Jang, highlight additional impactful implications stemming from their collaborative work, “Our findings showing that the FDA-approved A2AR antagonist istradefylline is preclinically effective against cisplatin-induced chemobrain, is an exciting prospect given that it is actively used for the treatment of Parkinson’s disease. This can facilitate rapid initiation of clinical trials, examining istradefylline’s efficacy in cancer survivors (a number estimated to increase to 22.1 million in the US by 2030).”

Commenting on the impact of The Bosarge Family Foundation-Waun Ki Hong Scholar Award for Regenerative Cancer Medicine on his career, Dr. Oliveros shared, “AACR grant support underscores the importance of the scientific questions I aimed to pursue – what are the underlying molecular neuropathologies driving chemobrain, and can we find novel treatment strategies to improve quality of life in cancer survivors? In addition, our findings have spurred new research directions; namely, the molecular and behavioral underpinnings of chemobrain in pediatric cancer models. Consequently, my AACR grant, a postdoctoral fellowship, strengthened the communication and research training relationship with my mentor. Boosted by this mutually beneficial mentor-mentee relationship, I endeavor to become a role model for my scientist mentees as well.”

Reference:

  1. Das A, Ranadive N, Kinra M, Nampoothiri M, Arora D, Mudgal J. An Overview on Chemotherapy-induced Cognitive Impairment and Potential Role of Antidepressants. Curr Neuropharmacol 2020; 18:838-51.
  2. Oliverosa A, Yooa KH, Rashida MA, Corujo-Ramirez A, Hur B, Sung J, et al. Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function. Proc Natl Acad Sci USA 2022; 119: e2206415119.
  3. Yoo KH, Tang JJ, Rashid MA, Cho CH, Corujo-Ramirez A, Choi J, et al. Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments. Cancer Res 2021; 81:3727-3737.
  4. Cunha RA. How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 2016; 139:1019-1055.