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Author ORCID Identifier

https://orcid.org/0009-0003-4093-0915

Date Available

7-3-2028

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Luksana Chaiswing

Faculty

Yekaterina Zaytseva

Abstract

Cognitive decline is an increasingly recognized complication of both brain tumors and their treatments, significantly impacting patient quality of life. Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Patients with brain cancer develop neurological symptoms like headaches, vision or balance alterations and cognitive decline, including speech difficulties and memory loss. However, the biological mechanisms underlying cancer- and treatment-associated cognitive impairment have not been elucidated. A deeper understanding of how tumor- and therapy-associated factors contribute to neurological alterations is critical for improving long-term quality of life in patients.

Extracellular vesicles (EVs) are membrane bound vesicles that cells release to the extracellular space. EVs have emerged as important mediators of intercellular communication and modifiers of the tumor microenvironment. Specifically, for GBM patients, the number of EVs in circulation is higher when compared to healthy individuals, yet, their potential contribution to cognitive dysfunction remains unclear. The findings of this dissertation provide insights into the mechanistic role of EVs in cognitive alterations in the context of GBM, showing how GBM-derived EVs are internalized by microglia, which become activated and in turn release hydrogen peroxide that is neurotoxic.

Additionally, therapeutic strategies developed for cancer treatment must also consider neurological effects and find alternatives for their mitigation. In GBM, the standard of care includes surgical resection, chemotherapy and radiation. The latter is frequently associated with long-term adverse cognitive outcomes. This work also evaluated how a novel therapeutic compound in combination with radiation affects cognitive outcomes and biological modifications in a model with GBM-derived EVs and a clinically relevant GBM model.

Together, this work advances the mechanistic understanding of cognitive dysfunction in GBM by examining both tumor-derived contributions and therapeutic effects. These findings contribute to optimizing cancer treatment while mitigating its impact on cognitive health, a critically understudied area of research.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.333

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Funding Information

This work was supported by: National Cancer Institute: CCSG P30 CA177558, R01 CA251663, National Instituted of Health S10OD032256 for SARRP, National Institute of General Medical Sciences: CNS Metabolism P20 GM148326, MCC-CCM P20 GM121327, 2023 Collaborative Bench to Bedside Radiation Medicine MCC, KY INBRE P20GM103436-24

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Available for download on Monday, July 03, 2028

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