Advisory Committee Chair
Markus Bredel
Advisory Committee Members
Anhita Hjelmeland
C Ryan Miller
Champion Deivanayagam
William Placzek
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Gliomas, and especially diffuse gliomas, can be a devastating disease when attempting treatment in the clinic. Diffuse gliomas are typically malignant and pose definitive problems with respect to patient care predominantly due to their ability to exist outside of the bulk tumor by invading into the surrounding brain parenchyma. Consequently, not every cancerous cell can be fully removed by surgical resection and therapeutic resistance, so the stem-like population left behind can repopulate a recurrent tumor from a single cell. There is a desperate need for pinpointing novel therapeutic vulnerabilities in diffuse gliomas, which could potentially involve the targeting of key genes essential for their survival. One avenue for augmenting the treatment efficacy for diffuse gliomas includes restoring or reintroducing tumor suppressors that are lost during gliomagenesis. Iκβa, encoded by the NFKBIA gene, is a well-known tumor suppressor that canonically sequesters NF-κB in the cytoplasm, preventing it from entering the nucleus to enact its transcription factor (TF) activity. However, we identified an arguably more prevalent mechanism for Iκβa entirely independent of NF-κB signaling that was further characterized via separation of function (SOF) mutants. We found demonstrated Iκβa capable of direct TF activity that could be the more catastrophic function of Iκβa being pruned during gliomagenesis to allow for diffuse glioma tumor growth. Another intriguing tumor suppressor gene for gliomas is ANXA7, which encodes for both isoforms of the Annexin A7 protein. As one of the members of the Annexin A family in humans, Annexin A7 has been understudied within the context of gliomas. This lapse in the literature should be filled when considering the alternative splicing of Annexin A7 can yield either full-length isoform 1 (I1) or isoform 2 (I2) that is generated through the skipping of cassette exon 6. We found I1 alone to facilitate the degradation of epidermal growth factor receptor (EGFR) following activation in clinically relevant glioma models. Determining which tumor suppressor genes are integral to gliomagenesis possesses unequivocal therapeutic potential for diffuse glioma patients, especially those of higher grade. We determined the significance of two distinct but uniquely prevalent tumor suppressors that are essential for glioma stem cell maintenance. Although there are more prevalent genes aside from just NFKBIA and ANXA7, our findings warrant the investigation into their clinical relevance. Developing therapies to target these tumor suppressors can potentially provide patients with better long-term survival. Furthermore, these tumor suppressors play a significant role in both low- and high-grade diffuse gliomas, including the most aggressive form known as glioblastoma. Successful rescuing of either of these tumor suppressors by any of the proposed therapeutic strategies could provide benefits for patients by significantly prolonging their overall survival.
Recommended Citation
Merati, Aran, "Investigating Potential Therapeutic Vulnerabilities And Elucidating Molecular Mechanisms For The Tumor Suppressors Nfkbia And Anxa7 In Diffuse Gliomas" (2025). All ETDs from UAB. 6870.
https://digitalcommons.library.uab.edu/etd-collection/6870
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