Restoring the Sphingolipid Balance in Glioblastoma

恢复胶质母细胞瘤中的鞘脂平衡

• 批准号: 10464055
• 负责人: Cyntanna Hawkins
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2022-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464055
• 关键词: Active Sites; Affect; Apoptosis; Apoptotic; Attenuated; Back; Binding; Brain; Brain Neoplasms; Cell Death; Cell Survival; Cells; Ceramidase; Ceramides; Data; Disease; Environment; Enzymes; Equilibrium; Excision; Genetic; Glioblastoma; Glioma; Glucose; Growth; Hydrolysis; Hypoxia; Immunosuppression; Ischemia; Knowledge; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Metabolism; Myocardial Infarction; Neurodegenerative Disorders; Nuclear; Operative Surgical Procedures; Pathway interactions; Patients; Pharmacology; Phenotype; Production; Radiation therapy; Radio; Regimen; Research; Resistance; SPHK1 enzyme; Signal Transduction; Sphingolipids; Sphingosine; Testing; The Cancer Genome Atlas; Therapeutic; Work; arginase; brain cell; cancer type; cell growth; cell motility; chemokine; chemotherapy; extracellular; galactosylgalactosylglucosylceramidase; genetic approach; improved; inhibitor; insight; macrophage; melanoma; migration; nerve stem cell; novel; patient derived xenograft model; recruit; sphingosine 1-phosphate; standard of care; stem-like cell; targeted treatment; temozolomide; therapeutically effective; treatment strategy; tumor; tumor microenvironment; tumorigenic

PROJECT SUMMARY/ABSTRACT The sphingolipid rheostat, which is the balance of ceramides and sphingosine-1-phosphate, is critical for regulating cell fate. Ceramides can be converted by ceramidases to sphingosine, which can then be converted by sphingosine kinase 1 to sphingosine-1-phosphate. Shifts toward sphingosine-1-phosphate production may allow cells to evade apoptosis and increase migration, while shifts toward ceramides may favor cell death. Dysregulated sphingolipid metabolism is associated with neurodegenerative disorders and cancer, although the sphingolipid rheostat is less well-studied in neural stem cells or brain tumors. The most common primary, malignant brain tumor is glioblastoma for which standard of care includes surgery, chemotherapy with temozolomide, and radiotherapy. This aggressive regimen fails to eradicate a subset of highly invasive, chemo- and radiotherapy resistant, neural stem cell-like, brain tumor initiating cells (BTICs) and glioblastoma quickly recurs. Radiotherapy can increase acid ceramidase (ASAH1) in BTICs, contributing to a shift in the sphingolipid balance towards sphingosine-1-phosphate. ASAH1 is highly expressed in glioblastoma and is associated with worse survival of glioma patients in The Cancer Genome Atlas data. ASAH1 inhibitors have been shown to increase pro-apoptotic ceramides and block the progression of some cancer types. We seek to determine whether an inhibitor of ASAH1, carmofur, is effective against BTICs derived from parental and temozolomide- resistant patient derived xenografts and to determine the impact of altered sphingolipid metabolism on glioblastoma migration and the brain tumor microenvironment. I anticipate that the studies proposed here will demonstrate that shifting the sphingolipid balance back toward ceramides is an effective therapeutic strategy in glioblastoma.

项目总结/摘要 神经酰胺和鞘氨醇-1-磷酸的平衡是鞘脂变阻器的关键， 调节细胞命运神经酰胺可以通过神经酰胺酶转化为鞘氨醇，然后可以将鞘氨醇转化为 由鞘氨醇激酶1转化为鞘氨醇-1-磷酸。向鞘氨醇-1-磷酸生产的转变可能 允许细胞逃避凋亡并增加迁移，而向神经酰胺的转变可能有利于细胞死亡。 鞘脂代谢失调与神经退行性疾病和癌症有关，尽管神经退行性疾病和癌症的发生与神经系统疾病有关。 鞘脂变阻器在神经干细胞或脑肿瘤中的研究较少。最常见的小学， 恶性脑肿瘤是胶质母细胞瘤，其护理标准包括手术、化疗和化疗。 替莫唑胺和放疗。这种积极的治疗方案未能根除一部分高度侵入性的化疗药物。 以及放射治疗抗性、神经干细胞样、脑肿瘤起始细胞（BTIC）和胶质母细胞瘤 复发放射治疗可增加BTIC中的酸性神经酰胺酶（ASAH 1），导致鞘脂转移， 向1-磷酸鞘氨醇平衡。ASAH 1在胶质母细胞瘤中高度表达， 在癌症基因组图谱数据中，胶质瘤患者的生存率更低。ASAH 1抑制剂已被证明 增加促凋亡神经酰胺并阻断某些癌症类型的进展。我们试图确定其 ASAH 1抑制剂卡莫氟是否能有效对抗源自母体和替莫唑胺的BTIC- 耐药患者来源的异种移植物，并确定改变的鞘脂代谢对 胶质母细胞瘤迁移和脑肿瘤微环境。我预计，这里提出的研究将 证明将鞘脂平衡向神经酰胺转移是一种有效的治疗策略， 胶质母细胞瘤