Consequences of metabolic reprogramming by GLUT3 in GBM

GBM 中 GLUT3 代谢重编程的后果

• 批准号: 9812767
• 负责人: Catherine J Libby
• 金额: $ 2.82万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-05-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812767
• 关键词: Address; Adult; Affinity; Animals; Astrocytes; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cells; Colon Carcinoma; Cues; Data; Disease; Ectopic Expression; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Fibronectins; Genes; Genus Hippocampus; Glioblastoma; Glioma; Glucose; Glucose Transporter; Growth; Head and Neck Cancer; Human; Immunoblotting; In Vitro; Invaded; Knowledge; Laminin; Learning; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of ovary; Mediating; Metabolic; Metabolism; Metastasis Suppression; Molecular; Mus; Nature; Neoplasm Metastasis; Neurons; Nutrient; Pathway interactions; Patients; Penetration; Pharmacology; Phenotype; Play; Property; Quantitative Reverse Transcriptase PCR; Recurrence; Research; Research Personnel; Role; SLC2A1 gene; Site; Solid Neoplasm; Specificity; Stains; Structure; Techniques; Tenascin; Therapeutic; Time; Toxic effect; Tumor Cell Invasion; Tumor Initiators; Tumor Promotion; Xenograft procedure; base; career; cell growth; glucose transport; glucose uptake; implantation; improved; in vivo; inhibitor/antagonist; knock-down; metabolic profile; metabolomics; neoplastic cell; nerve stem cell; novel; novel therapeutics; outcome forecast; overexpression; preclinical trial; protein expression; response; self-renewal; single cell analysis; small hairpin RNA; small molecule; therapy development; therapy resistant; transport inhibitor; tumor; tumor growth; tumor heterogeneity; tumor metabolism; tumor microenvironment; tumor progression; tumorigenic

ABSTRACT Glioblastoma (WHO grade IV astrocytoma; GBM) is the most common and deadly primary malignant brain tumor in adults. Therapy development has been hampered by the heterogeneous nature of GBM. Within GBM, a subset of tumor cells known as brain tumor initiating cells (BTICs) are highly tumorigenic and have some properties of neural stem cells. By co-opting the high affinity neuronal glucose transporter type 3 (GLUT3) brain tumor initiating cells (BTICs) can preferentially survive in low nutrient tumor microenvironments; leading to tumor promotion and progression. GLUT3 expression in many solid tumor types such as GBM, colon cancer, head and neck cancers and ovarian cancer is correlated with poor prognosis and survival. High GLUT3 expression also correlates with metastatic or invasive disease. The relationship between GLUT3 expression and invasion in GBM has not been explored. In this study, we aim to understand the role of metabolic reprogramming by GLUT3 in the invasion of GBM and explore opportunities for the pharmacological targeting of GLUT3 . We have identified novel GLUT3 inhibitors that are able to preferentially inhibit the growth and glucose up take of BTICs with little toxicity to non-neoplastic cells. Through this study, we hope to understand the role of GLUT3 in tumors and to identify a potential new therapeutic option to target metabolic reprogramming for the treatment of GBM.

摘要 胶质母细胞瘤（WHO IV级星形细胞瘤; GBM）是最常见和致命的原发性脑恶性肿瘤 成人肿瘤GBM的异质性阻碍了治疗的发展。内 GBM是一种称为脑肿瘤起始细胞（BTIC）的肿瘤细胞亚群，具有高度致瘤性， 神经干细胞的一些特性通过选择高亲和力神经元葡萄糖转运蛋白3 （GLUT 3）脑肿瘤起始细胞（BTIC）可以优先在低营养肿瘤微环境中存活; 导致肿瘤的促进和发展。GLUT 3在许多实体瘤类型中的表达，例如GBM、结肠 癌症、头颈癌和卵巢癌与预后和存活率差相关。高GLUT 3 表达也与转移性或侵袭性疾病相关。GLUT 3表达与 GBM中的侵袭尚未被探索。在这项研究中，我们的目标是了解代谢的作用， GLUT 3在GBM侵袭中的重编程，并探索药物靶向的机会。 关于GLUT 3我们已经鉴定了能够优先抑制生长的新型GLUT 3抑制剂， BTIC的葡萄糖摄取对非肿瘤细胞几乎没有毒性。通过这项研究，我们希望了解 GLUT 3在肿瘤中的作用，并确定一种潜在的新的治疗选择，以靶向代谢 重编程用于治疗GBM。