Advisory Committee Chair
Anita B Hjelmeland
Advisory Committee Members
Etty (Tika) Benveniste
Kai Jiao
Louis B Nabors
Hengbin Wang
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor initiating cell hypothesis. The ischemic microenvironment characterized by low oxygen and glucose, and acidic stress occurs in both solid tumors and non-neoplastic tissue injury. Standard of care for glioblastoma (GBM) includes the chemotherapy temozolomide, which is not curative due, in part, to residual therapy-resistant brain tumor initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CAIX), a hypoxia and acidic stress responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether the CAIX/XII inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs post-chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a less energetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment as determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM bearing mice and should be explored as a novel treatment strategy in combination with current standard of care. By modeling physiologic microenvironments in GBM in vitro, we identified chromodomain helicase DNA binding protein 7 (CHD7) as a novel ischemia-regulated epigenetic modifier. Microenvironment-mediated decreases in CHD7 occurred in GBM and neural progenitor cells in vitro, and in perinecrotic niches of GBM patient sections. Genetic targeting of CHD7 increased angiogenesis in association with differential regulation of angiogenesis associated genes. Analysis of GBM patient datasets revealed worse patient outcomes with low expression of CHD7. Together, our data provide insight into the molecular responses to ischemia that regulate GBM growth and angiogenesis and provide opportunities for therapeutic intervention.
Recommended Citation
Boyd, Nathaniel H., "Microenvironmental Regulation And Epigenetic Control Of Glioma Pathogenesis" (2017). All ETDs from UAB. 1232.
https://digitalcommons.library.uab.edu/etd-collection/1232