Mechanistic insights into chemotherapy-induced cognitive impairment

Current chemotherapy regimens have significantly improved overall survival for children with cancer. However, these curative treatments are associated with detrimental side effects such as chemotherapy-induced cognitive impairment (CICI). Measurable deficits in cognitive function may persist years after chemotherapy treatments, significantly reducing quality of life. Specifically, methotrexate (MTX) and doxorubicin (DOXO), two commonly used chemotherapeutic agents in curative regimens for children with cancer, play a pivotal role in the development of CICI, even though neither drug crosses the blood-brain barrier (BBB) substantially. This dissertation investigated MTX- and DOXO-related CICI in an effort to better define the underlying pathophysiology. Our earliest work involved MTX to model a low-dose treatment regimen for pediatric acute lymphoblastic leukemia (ALL) patients and investigated the long-lasting cognitive deficits by assessing cognitive function and the associated neuropathology across multiple time points after MTX exposure. Our findings provide insights into the underlying cause of MTX-induced cognitive deficits, which persisted for more than one year post-MTX exposure. Our studies then turned to exploring the changes induced by DOXO in BBB integrity in vitro, using human cerebral microvascular endothelial cells (hCMEC/D3). DOXO treatment induced mitochondrial dysfunction, a subsequent dysregulation of genes related to BBB maintenance, and activation of signaling pathways that confirmed an inflammatory state in hCMEC/D3. Our results provide critical insights on how DOXO impacts the BBB and build a foundation for developing preventative measures and therapeutic interventions that may improve the quality of life for patients. In order to better understand interpatient variability in cognitive outcomes among cancer survivors, we studied the impact of one common gene variant on CICI in a novel, juvenile animal model. Apolipoprotein E (ApoE) has been identified as a risk variant among pediatric cancer survivors, with the ApoE4 allele being associated with increased vulnerability to CICI. We tested whether harboring the ApoE4 allele would increase sensitivity to DOXO-induced cognitive impairment and exacerbate the associated neuropathology in a juvenile ApoE4 rat model. Our findings suggest that the ApoE genotype influences vulnerability to CICI and highlights a potential mechanistic link through impaired neurogenesis, laying the groundwork for genotype-specific therapeutic strategies. In addition, this dissertation delved into the role of the gut microbiome in DOXO-induced toxicity. A growing body of literature suggests that the gut microbiome modulates chemotherapy-induced side effects or physiologies; however, it is not clearly understood how the gut microbiome is associated with these side effects. There may be a plausible association between ApoE alleles and the gut microbiome. Here, we investigated the impact of DOXO on the gut microbiome and whether harboring the ApoE4 allele increased sensitivity to these changes. These results set the stage for further investigations of how chemotherapy-induced changes in gut microbiome might contribute to CICI and point toward therapeutic interventions. Collectively, this dissertation provides a better understanding of the molecular mechanisms related to CICI. It also allows us to identify a subset of patients who are more susceptible and provides insights for potential novel therapeutic targets to improve the clinical treatment of CICI and the quality of life for patients.