Glioblastoma multiform (GBM) is the most common primary malignant brain tumor in adults and among the deadliest cancers due, in part, to therapeutic resistance and tumor recurrence. One compelling reason therapy development has proven challenging is the heterogeneous nature of GBMs. These malignancies contain a subset of tumor cells known as brain tumor initiating cells (BTICs) that are highly tumorigenic due to an ability to promote tumor angiogenesis and have some properties of non-neoplastic neural stem cells. BTICs have a unique ability to survive in a distinct tumor microenvironments characterized as either vascular or necrotic/hypoxic niches. The necrotic/hypoxic niches contain levels of acidity greater than physiologic norms, and low extracellular pH contributes to tumor growth and enriches for BTIC phenotypes. Epigenetic mechanisms contributing to these microenvironmental pressures have not been elucidated. In this study, a molecular target that has been identified as a chromatin remodeler will be investigated to determine its role in regulating angiogenesis. We will also target the acidic tumor microenvironment to determine if the modulation of intratumoral pH can be a benefit to therapeutic strategies. Through this study we hope to achieve a greater understanding of the contribution of acidic microenvironments to epigenetic changes and develop a novel treatment strategy to target angiogenesis in patient therapies.
Regions of low oxygen, acidity, and depleted nutrient levels are often present in brain tumors. The effects of these regions on brain tumor cells is poorly understood because they are not often modeled in the laboratory. We have discovered a new way acidity may affect the growth of brain tumors and have developed a new approach to target brain tumors that may provide novel treatment strategies for brain tumor patients.
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| Tran, Anh N; Boyd, Nathaniel H; Walker, Kiera et al. (2017) NOS Expression and NO Function in Glioma and Implications for Patient Therapies. Antioxid Redox Signal 26:986-999 |
| Gilbert, Ashley N; Walker, Kiera; Tran, Anh Nhat et al. (2017) Modeling Physiologic Microenvironments in Three-Dimensional Microtumors Maintains Brain Tumor Initiating Cells. J Cancer Stem Cell Res 5: |
