Date of Award
5-2025
Document Type
Thesis
Degree Name
Master of Science in Biology
Department
Biology
First Reader/Committee Chair
Bournias-Vardiabasis, Nicole (Ph.D., Dr.)
Abstract
Glioblastoma (GBM) is a highly aggressive brain tumor that remains a significant challenge in neuro-oncology today. Approximately 90% of GBM patients experience tumor recurrence within one to two years of diagnosis. Therefore, due to its high resistance to conventional therapies, new treatment strategies are urgently needed. The current standard of care for GBM is the chemotherapeutic Temozolomide (TMZ). TMZ is an oral alkylating agent, it functions by delivering a methyl group to purine bases. The development of resistance to TMZ is partially regulated by the DNA repair enzyme O6- methylguanine-DNA methyltransferase (MGMT). Despite the potential shown by MGMT promoter methylation in enhancing patient survival, recent studies have revealed its low predictive value in GBM patients. MGMT hypermethylation often leads to resistance by activating DNA repair pathways. Glioma stem cells (GSCs) contribute to chemoresistance and tumor heterogeneity due to their self-renewal capacity and activation of DNA repair responses to overcome radiation and TMZ treatment. These resistance defenses contribute to tumor recurrence and highlight a need for potential therapies in GBM.
MAGMAS, a 13.8 kDa mitochondria trafficking protein, regulates the ATP stimulatory activity of mitochondrial import inner membrane translocase subunit Tim14 on mtHSP70 and oxidative phosphorylation via interactions with the respiratory complexes in the inner mitochondrial membrane. Previously, our lab has demonstrated that MAGMAS is overexpressed in GBM patients' tissues and mouse xenografts. Furthermore, the pharmacological inhibition of MAGMAS through the novel compound, BT9, has been shown to promote cytotoxicity and impair respiratory functions in malignant glioma cells, underscoring its therapeutic potential in GBM. However, further studies are needed to fully understand the role of MAGMAS, from initial tumor progression to its implication in the development of treatment resistance.
Our study's main objective is to understand the role of MAGMAS in the development of TMZ resistance. Our preliminary data, comparing temozolomide- resistant (TR) GBM cell lines, U251-TR and D54 MG-TR, with their drug- sensitive parental cell lines (S), shows a significant upregulation of MAGMAS in the TR cell lines compared to the S lines. To study alternative DNA repair mechanisms and their contribution to chemoresistance, we incorporated an additional clinically relevant model, cell lines resistant to TMZ in presence of O6- benzylguanine (O6-BG, MGMT inhibitor), OTR lines. Since O6-MG inhibits MGMT, OTR cell lines acquire TMZ resistance through alternative DNA repair pathways. MAGMAS mRNA expression is significantly higher in both TR and OTR in comparison to S cells. This observation led to our hypothesis that MAGMAS inhibition could potentially re-sensitize TR and OTR GBM cell lines to TMZ. Our findings support this hypothesis, as we demonstrate that MAGMAS pharmacological inhibition, using BT9, sensitizes chemoresistant cell lines, TR and OTR, to TMZ. These results suggest that a combination therapy based on MAGMAS inhibition and TMZ might offer an increased benefit when used in combination to treat TMZ-resistant GBM.
Recommended Citation
Tran, Jennifer Duyen, "The Development of MAGMAS Inhibition as a Potential Therapeutic Target in Temozolomide Resistant Glioma" (2025). Electronic Theses, Projects, and Dissertations. 2116.
https://scholarworks.lib.csusb.edu/etd/2116
Included in
Cancer Biology Commons, Cell Biology Commons, Therapeutics Commons, Translational Medical Research Commons
