Locally reduced oxygen levels are a feature of many malignancies, particularly those which grow rapidly. One cancer in which hypoxia-induced necrosis and neovascularization is central to pathological diagnosis is glioblastoma the most common malignant brain tumor. Hypoxic regions are frequent in glioblastoma, and increased levels of tumor hypoxia have been associated with worse clinical outcomes. In this proposal, we focus on functionally important links between hypoxia, the monocarboxylate transporter-4 (MCT4), and Notch and their role in promoting the growth and survival of stem-like glioma cells (GSC) in malignant brain tumors for which there is no cure. In the first aim we determine how Notch is regulated by MCT4.
In Aim 2, we will study the relationship between Notch and GSC in the hypoxic microenvironment. Finally, in Aim 3 we will focus on potential mechanism by which MCT4 may regulate GSC radiation sensitivity. These studies build directly on recent work from our group linking hypoxia, Notch, and MCT4 to stem cell induction and address the role of MCT4 in mediating critical aspects of the hypoxic response. An important component of our strategy is using novel constructs to manipulate and measure the molecular response to hypoxia and Notch signaling. We hope that these studies will lay the foundation for direct translation into clinical therapeutic trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA187780-06
Application #
10071001
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Salnikow, Konstantin
Project Start
2015-06-01
Project End
2020-05-31
Budget Start
2019-12-16
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Pathology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Boyd, Nathaniel H; Walker, Kiera; Fried, Joshua et al. (2017) Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight 2:
Voss, Dillon M; Spina, Raffaella; Carter, David L et al. (2017) Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression. Sci Rep 7:4292
Zhang, Ying; Cruickshanks, Nichola; Yuan, Fang et al. (2017) Targetable T-type Calcium Channels Drive Glioblastoma. Cancer Res 77:3479-3490
Ismael, Amber; Tian, Wei; Waszczak, Nicholas et al. (2016) G? promotes pheromone receptor polarization and yeast chemotropism by inhibiting receptor phosphorylation. Sci Signal 9:ra38
Spina, Raffaella; Voss, Dillon M; Asnaghi, Laura et al. (2016) Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells. Oncotarget 7:459-72