Extracellular Vesicles as Biomarker Carriers in Central Nervous System Malignancy
Open Access
- Author:
- Khristov, Vladimir
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 16, 2022
- Committee Members:
- Jeffrey Sundstrom, Outside Unit & Field Member
Elizabeth Proctor, Major Field Member
James Connor, Chair & Dissertation Advisor
Brad Zacharia, Special Member
Ralph Keil, Program Head/Chair
Vladimir Spiegelman, Major Field Member - Keywords:
- glioblastoma
liquid biopsy
brain tumor
extracellular vesicle
biomarker - Abstract:
- There is a pressing clinical need for minimally-invasive liquid biopsies to supplement imaging in the treatment of glioblastoma (GBM) and other malignancies of the central nervous system. Diagnostic imaging is often difficult to interpret and it remains a challenge to define response rates and progression versus treatment effect. Further, imaging methods are limited in their capacity to detect minimal residual disease. The “liquid biome” is the combination of biological fluids including blood, urine, and cerebrospinal fluid (CSF) that contain small amounts of tumor cells, DNA/RNA coding material, peptides, and metabolites. Within the liquid biome two broad categories of biomarkers can exist: tumor-derived which can be directly traced to the tumor and tumor-associated which can be traced back to the response of the body to disease. While tumor-associated biomarkers are promising liquid biopsy candidates, recent advances in biomarker enrichment and detection have allowed us to concentrate on a new class of biomarker – tumor-derived biomarkers. A minimally-invasive liquid biopsy would supplement imaging and clinical findings and has the capacity to be helpful in several ways: 1) diagnosis, 2) selection of patients for specific treatments, 3) tracking of treatment response, and 4) prognostic value. In my thesis, I aimed to address several pressing questions in the field of CNS tumor liquid biopsy from multiple directions and experimental models . I first set the stage by reviewing existing scientific literature on the topic of GBM liquid biopsy. After seeing that the field of protein liquid biopsy biomarkers for GBM remains relatively underexplored, I conduct a pilot study for the utility of a previously-unvalidated biomarker IL13Rα2, which shows diagnostic and prognostic significance. Next, I explore the question of optimal biofluid selection in CNS malignancy by studying matched CSF-plasma sample pairs in patients with CNS lymphoma. Finally, I explore a common class of medications and their double ability to act as potential confounding factors in the study of liquid biopsy biomarkers, while providing therapeutic benefit to the patients.