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Restoring the Sphingolipid Balance in Glioblastoma

恢复胶质母细胞瘤中的鞘脂平衡

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要鞘脂变阻器是神经酰胺和 1-磷酸鞘氨醇的平衡，对于神经酰胺和 1-磷酸鞘氨醇的平衡至关重要。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，然后再转化为鞘氨醇通过鞘氨醇激酶 1 转化为 1-磷酸鞘氨醇。转向 1-磷酸鞘氨醇生产可能允许细胞逃避凋亡并增加迁移，而转向神经酰胺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。最常见的初级，恶性脑肿瘤是胶质母细胞瘤，其标准护理包括手术、化疗替莫唑胺和放射治疗。这种积极的治疗方案未能根除一部分高侵袭性、化疗性的疾病。快速抗放疗、神经干细胞样、脑肿瘤起始细胞 (BTIC) 和胶质母细胞瘤重复出现。放射治疗可以增加 BTIC 中的酸性神经酰胺酶 (ASAH1)，从而导致鞘脂发生变化 1-磷酸鞘氨醇的平衡。 ASAH1 在胶质母细胞瘤中高表达，并与癌症基因组图谱数据中神经胶质瘤患者的生存率较差。 ASAH1 抑制剂已被证明可以增加促凋亡神经酰胺并阻止某些癌症类型的进展。我们寻求确定 ASAH1 抑制剂卡莫氟是否对源自亲本和替莫唑胺的 BTIC 有效？耐药患者来源的异种移植物并确定鞘脂代谢改变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转向神经酰胺是一种有效的治疗策略胶质母细胞瘤。