Metabolic Resistance to Hypoxia in Glioblastoma Multiforme

多形性胶质母细胞瘤对缺氧的代谢抵抗

• 批准号: 10098011
• 负责人: Laura Caflisch
• 金额: $ 4.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10098011
• 关键词: Address; Alkylating Agents; Angiogenesis Inhibitors; Biology; Catabolism; Cell Hypoxia; Cells; Characteristics; Common Neoplasm; Consumption; Data; Disease; Energy-Generating Resources; Environment; Excision; Exposure to; Family; Fatty Acids; Genes; Glioblastoma; Glycolysis Induction; Growth; Hypoxia; In Vitro; Investigation; Knowledge; Length; Lipids; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Messenger RNA; Metabolic; Metabolic Pathway; Mitochondria; Newly Diagnosed; Operative Surgical Procedures; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Personal Satisfaction; Physicians; Production; Prognosis; Radiation therapy; Recurrence; Recurrent tumor; Research; Research Personnel; Resistance; Resistance development; Role; Scientist; Source; Stromal Cells; Translating; Treatment Protocols; Triglycerides; Very Long Chain Fatty Acid; Work; bevacizumab; cancer therapy; cell growth; combat; design; efficacy testing; experience; extracellular vesicles; fatty acid oxidation; improved; in vivo; inhibitor/antagonist; innovation; lipid metabolism; mRNA Expression; metabolomics; prostate cancer cell; skills; temozolomide; therapy design; therapy resistant; treatment strategy; tumor; tumor growth; tumor hypoxia

Abstract The malignant brain tumor Glioblastoma (GBM) is a tragic illness for patients and families due to poor patient prognosis, with only 9.8% of patients surviving past 5 years. Only modest gains in survival have been made despite decades of research, therefore, a better understanding of the basic biology of this disease is needed to improve patient outcomes. Hypoxia is characteristic of GBM and many other tumors, and is increased by the anti-angiogenic agent bevacizumab, which is commonly used for recurrent GBM tumors. Metabolic changes contribute to adaptation to tumor hypoxia, and can be potentially targeted to reduce treatment resistance. Our preliminary data shows elevated levels of triglycerides and decreased levels of very long chain fatty acids in highly hypoxic tumors. This suggests the use of peroxisomal fatty acid oxidation which primarily catabolizes very long chain fatty acids, as a fuel source in highly hypoxic tumors. In addition, previous studies show that hypoxia induces secretion of triglyceride-loaded extracellular vesicles in prostate cancer cells. Triglyceride-loaded extracellular vesicles may be a potential mechanism for delivering fuel sources to GBM cells during hypoxia. We hypothesize that GBM cells rely on peroxisomal fatty acid oxidation and triglyceride-loaded extracellular vesicle secretion to fuel tumor growth during hypoxia. We will investigate this hypothesis through our specific aims: 1) determine the effect of peroxisomal fatty acid oxidation in adaptation to hypoxia induced by anti-angiogenic treatment in GBM tumors, and 2) define the role of extracellular vesicle formation and lipid secretion in adaptation to hypoxia induced by anti-angiogenic treatment in GBM tumors. To address both of these specific aims, we will 1) determine the lipid metabolism effects of hypoxia on cells and extracellular vesicles in vitro using metabolomics and mRNA analysis, and 2) test the efficacy of combining inhibitors targeting peroxisomal fatty acid oxidation or triglyceride synthesis with anti-angiogenic treatment both in vitro and in vivo. When using these inhibitors, we expect to see 1) inhibition of cell growth in vitro in cells exposed to hypoxia, and 2) inhibition of tumor growth and extension of survival for tumors treated with anti-angiogenic treatment and our inhibitory agents, compared to either treatment alone. These studies are significant in that they will elucidate mechanisms for tumor growth and resistance to treatment. The identified mechanisms can be targeted and incorporated into innovative treatment regimens for GBM patients, potentially leading to substantial increases in survival and patient well-being.

摘要 恶性脑肿瘤胶质母细胞瘤（GBM）是一个悲惨的疾病，病人和家庭，由于穷人的病人 预后，只有9.8%的患者存活超过5年。在生存方面只取得了有限的进展 因此，尽管进行了数十年的研究，但仍需要更好地了解这种疾病的基本生物学， 改善患者预后。缺氧是GBM和许多其他肿瘤的特征，并且随着GBM的生长而增加。 抗血管生成剂贝伐单抗，其通常用于复发性GBM肿瘤。代谢变化 有助于适应肿瘤缺氧，并且可以潜在地靶向降低治疗抗性。我们 初步数据显示，甘油三酯水平升高，极长链脂肪酸水平降低， 高度缺氧的肿瘤这表明使用过氧化物酶体脂肪酸氧化，其主要分解代谢非常 长链脂肪酸，作为高度缺氧肿瘤的燃料来源。此外，先前的研究表明， 在前列腺癌细胞中诱导分泌负载有磷脂酰肌醇的细胞外囊泡。载甘油三酯 细胞外囊泡可能是在缺氧期间向GBM细胞递送燃料源的潜在机制。我们 假设GBM细胞依赖于过氧化物酶体脂肪酸氧化和负载磷脂酰胆碱细胞外囊泡 在缺氧期间分泌以促进肿瘤生长。我们将通过我们的具体目标来研究这一假设：1） 确定过氧化物酶体脂肪酸氧化在抗血管生成药物诱导的缺氧适应中的作用 GBM肿瘤的治疗，以及2）确定细胞外囊泡形成和脂质分泌在适应中的作用 GBM肿瘤中抗血管生成治疗诱导的缺氧。为了实现这两个具体目标，我们将 1)用脂质体法测定缺氧对体外细胞和细胞外囊泡脂质代谢的影响， 代谢组学和mRNA分析，和2）测试靶向过氧化物酶体脂肪酸的组合抑制剂的功效， 酸氧化或甘油三酯合成，并在体外和体内进行抗血管生成治疗。当使用这些 抑制剂，我们期望看到1）在暴露于缺氧的细胞中抑制体外细胞生长，和2）抑制 用抗血管生成治疗和我们的抑制剂治疗的肿瘤的肿瘤生长和生存期延长 与单独治疗相比。这些研究意义重大，因为它们将阐明 肿瘤的生长和对治疗的抵抗。确定的机制可以有针对性地纳入 GBM患者的创新治疗方案，可能导致生存率的大幅提高， 病人的幸福。