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Date of Award
Summer 8-11-2025
Thesis Access
WSU Access Only Honors Thesis
Thesis Location
Honors College Thesis
Degree Name
B.S.
Department
Cancer Biology
Faculty Advisor
Dr. Ana deCarvalho
Abstract
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults, characterized by marked heterogeneity, treatment resistance, and poor prognosis. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key mediator of non-homologous end joining (NHEJ), the primary DNA double-strand break repair pathway in non-dividing cells. Its overactivity in GBM supports rapid repair of therapy-induced DNA damage, contributing to resistance against radiation and chemotherapy. This study investigated the therapeutic potential of DNA-PKcs inhibition in two patient-derived xenograft (PDX) models, HF3016 (newly diagnosed) and HF3177 (recurrent), originating from the same patient and both harboring TP53 mutations. Stable knockdown of PRKDC was achieved via shRNA, and its effects were evaluated in vivo using radiation, temozolomide (TMZ), or abemaciclib.
Knockdown alone did not improve survival, but in combination with radiation, DNA-PKcs suppression markedly sensitized tumors, particularly in HF3177-KD2, where deep and sustained knockdown was associated with durable, tumor-free survival in a subset of mice. In contrast, partial knockdown (HF3177-KD1) allowed post-radiation rebound of DNA-PKcs expression, limiting therapeutic benefit. HF3016 demonstrated additive effects of knockdown and radiation, with reductions in DNA-PKcs expression but no further suppression beyond baseline knockdown levels.
These findings highlight the importance of knockdown depth, context-specific responses, and the potential for selection of resistant clones when suppression is incomplete. DNA-Pkcs inhibition appears most effective as an adjunct to radiotherapy, but optimal benefit may require agents with robust brain penetrance and strategies to prevent compensatory repair pathway activation. This work supports further evaluation of DNA-PKcs as a therapeutic target in GBM and informs the design of biomarker-driven combination regimens.
Recommended Citation
Sogbesan, Olutomi, "EVALUATING DNA-PKCS INHIBITION AS A THERAPEUTIC STRATEGY IN TP53-MUTANT GLIOBLASTOMA" (2025). Honors College Theses. 95.
https://digitalcommons.wayne.edu/honorstheses/95