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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.

项目摘要/摘要鞘磷脂变阻器是神经酰胺和鞘氨醇-1-磷酸的平衡，对调节细胞的命运。神经酰胺可以被神经酰胺酶转化为鞘氨醇，然后再转化为鞘氨醇。由鞘氨醇激酶1转化为鞘氨醇-1-磷酸。转向生产鞘氨醇-1-磷酸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。神经鞘脂代谢失调与神经退行性疾病和癌症有关，尽管鞘磷脂变阻器在神经干细胞或脑肿瘤中的研究较少。最常见的初选，恶性脑瘤是一种胶质母细胞瘤，其标准护理包括手术、化疗和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度侵袭性的化疗-- 和放射耐受，神经干细胞样细胞，脑肿瘤启动细胞(BTICs)和胶质母细胞瘤迅速反复发作。放射治疗可增加BTIC中的酸性神经酰胺酶(ASAH1)，从而导致鞘磷脂的移位平衡神经鞘氨醇-1-磷酸。ASAH1在胶质母细胞瘤中高表达，并与在癌症基因组图谱数据中，胶质瘤患者的存活率较差。ASAH1抑制剂已被证明可以增加促细胞凋亡的神经酰胺，阻止某些癌症类型的进展。我们试图确定 ASAH1的抑制剂卡莫氟对母体和替莫唑胺产生的BTICs是否有效- 耐药患者来源的异种移植物，并确定鞘磷脂代谢改变对胶质母细胞瘤迁移与脑肿瘤微环境。我预计这里提出的研究将证明将鞘磷脂平衡重新转向神经酰胺是一种有效的治疗策略胶质母细胞瘤。