Advisory Committee Chair
Christopher Willey
Advisory Committee Members
Alexa Mattheyses
Anita Hjelmeland
Christian Faul
Vladimir Parpura
William Placzek
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Glioblastoma (GBM) is the most common primary brain malignancy in adults and the gradual development of treatment resistance prevents patients from achieving remission. A primary objective in the field is to devise strategies to overcome this. We predicted this could be achieved by improving existing therapies, creating better models to study GBM, and by identifying a potential therapeutic target. Fractionated radiotherapy (RT) has been used in GBM standard of care for over a century but does not account for GBM heterogeneity. We first hypothesized that in silico mathematical modeling would be a useful tool for cytotoxicity prediction. While this model had been investigated before, it remained elusive if the predictions translated to physiological systems. We used three patient-derived brain tumor-initiating cell (BTIC) xenolines with differential RT-sensitivity and a novel longitudinal imaging assay to answer this question. Key findings in this study revealed delivering RT in ramped down fractions overcame acquired radioresistance more efficiently than delivering equivalent fractions. Next, we aimed to design an improved pre-clinical in vitro model that better recapitulated GBM heterogeneity. We predicted this could be accomplished by formulating a special maintenance media that supports the stemness properties of BTICs and the canonical functions of astrocytes and macrophages. We validated our model using gold standard functionality assays and differential gene expression analysis which revealed our triculture model recapitulates GBM signatures better than GBM monocultures. Finally, we aimed to uncover a therapeutic target and mechanism. Tunneling nanotubes (TNT) are exciting due to their novelty, multifaceted utility in cellular processes, and therapeutic potential. In this study we aimed to elucidate the role of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) in the regulation of TNTs between GBM cells and astrocytes. Our results revealed TNT formation is influenced by PKC activation, MARCKS expression, and phosphorylation. Importantly, we were able to target the TNTs with a cytotoxic peptide derived from the effector domain of MARCKS, revealing therapeutic potential. In summation, the work presented in this thesis is geared towards assessing three key hypotheses that share the common goal of contributing to the attenuation of therapeutic resistance.
Recommended Citation
Nassour-Caswell, Lauren Catherine, "Therapeutic Implications Of Fractionated Radiotherapy And Marcks’ Regulation Of Tunneling Nanotubes In Glioblastoma" (2025). All ETDs from UAB. 6875.
https://digitalcommons.library.uab.edu/etd-collection/6875
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