The brain is one of the most metabolically active organs with glucose representing the most important, but not the only, source of energy and carbon. Like all cancers, glioblastoma, the most prevalent and malignant primary brain tumor, requires a continuous source of energy and molecular resources for new cell production with a preferential use of aerobic glycolysis, recognized as the Warburg effect. Aerobic glycolysis diminishes the need for oxygen, while inefficient liberation of energy permits residual carbons to be shunted to produce cellular components. Glioblastoma is a highly lethal cancer type with almost all targeted therapeutics tested to date showing minimal to no sustained clinical benefit. The failure to achieve cure has many causes, but we and others have linked self-renewing, highly tumorigenic glioma stem cells (GSCs) to therapeutic resistance, invasion into normal tissues, and increased angiogenesis. Targeting GSCs can inhibit tumor growth and sensitize tumors to conventional therapies. In this application, two leading GSC laboratories with complementary research foci have joined forces to examine the relationship between GSCs and metabolism. Isocitrate dehydrogenase 1 (IDH1) mutations directly link transformation and metabolism in low grade gliomas and secondary glioblastoma, but these mutations are relatively rare in glioblastoma, suggesting that alternative metabolic alterations are likely present. Our two groups have interrogated GSC glucose metabolism within the cellular hierarchy (intratumoral heterogeneity) and between tumors (intertumoral heterogeneity). In preliminary studies, we found that nutrient restriction mimicking tumor conditions enriches for GSCs through preferential GSC survival and acquisition of stem- like features in differentiated cells. GSCs respond to low glucose by preferential uptake of glucose through the expression of a specialized, high affinity neuronal glucose transporter (Glut3). Glut3 enriches for GSCs and targeting Glut3 expression attenuates stem cell self-renewal and tumor growth. GSCs are not static, but rather evolve during treatment. GSCs from proneural and mesenchymal glioblastomas display differential gene expression profiles and radiation sensitivity with increased glycolytic activity in mesenchymal GSCs. Radiation induces a proneural-to-mesenchymal transition associated with activation of glycolytic metabolism and aldehyde dehydrogenase activity. As selected metabolic nodes are amenable to therapeutic targeting, we hypothesize that the Warburg effect causally contributes to glioma heterogeneity through cellular hierarchical and clonal evolution mechanisms. In this application, the first aim will determine the tumor microenvironment reprograms glucose uptake to instruct glioblastoma cellular hierarchies. As an independent yet complementary study, the second aim will determine the role of glycolytic reprogramming in the evolution of glioma stem cells to acquire therapeutic resistance. The ultimate goals of these studies are to establish a new concept by incorporating both the cellular hierarchical theory and the clonal evolution theory to better clarify the mechanism of tumor heterogeneity and to establish targeted therapies for distinct molecules that are responsible for a gain of resistance t current therapies. The proposed studies, when completed, will challenge the current research and clinical practice hurdles and will create a firm path to translation by developing a novel strategy to target the newly identified metabolic alterations in glioblastomas.

Public Health Relevance

Glioblastomas are deadly cancers that are resistant to currently used therapies supporting the urgent need for new treatments. Glioblastomas, like many cancers, contain cells that share similarities with normal stem cells and display resistance to radiation and chemotherapy supporting the concept of these so called cancer stem cells as possible targets. We are investigating the role of cellular metabolism in the growth and resistance of glioblastoma cancer stem cells.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS087913-01
Application #
8722074
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Dermawan, Josephine Kam Tai; Hitomi, Masahiro; Silver, Daniel J et al. (2016) Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models. Cancer Res 76:2432-42
Cheng, Peng; Wang, Jia; Waghmare, Indrayani et al. (2016) FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells. Cancer Res 76:7219-7230
Hubert, Christopher G; Rivera, Maricruz; Spangler, Lisa C et al. (2016) A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo. Cancer Res 76:2465-77
Kim, Sung-Hak; Ezhilarasan, Ravesanker; Phillips, Emma et al. (2016) Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner. Cancer Cell 29:201-13
Xie, Qi; Wu, Qiulian; Kim, Leo et al. (2016) RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest 126:2757-72
Mack, Stephen C; Hubert, Christopher G; Miller, Tyler E et al. (2016) An epigenetic gateway to brain tumor cell identity. Nat Neurosci 19:10-9
Gallego-Perez, Daniel; Chang, Lingqian; Shi, Junfeng et al. (2016) On-Chip Clonal Analysis of Glioma-Stem-Cell Motility and Therapy Resistance. Nano Lett 16:5326-32
Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro et al. (2016) Senescence from glioma stem cell differentiation promotes tumor growth. Biochem Biophys Res Commun 470:275-81
Ahluwalia, Manmeet S; Rich, Jeremy N (2015) Growth Factor Receptor Fusions Predict Therapeutic Sensitivity. Clin Cancer Res 21:3105-7
Mack, Stephen C; Rich, Jeremy N; Scacheri, Peter C (2015) "PEAR-ing" Genomic and Epigenomic Analyses for Cancer Gene Discovery. Cancer Discov 5:1018-20

Showing the most recent 10 out of 33 publications