Anti-tumor Activity of Sugar Analogs via Blocking Glycolysis vs Glycosylation

糖类似物通过阻断糖酵解与糖基化的抗肿瘤活性

• 批准号: 7462352
• 负责人: THEODORE J LAMPIDIS
• 金额: $ 34.33万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462352
• 关键词: Aerobic; Apoptosis; Apoptotic; Area; Biological Assay; Carbon; Cell Line; Cells; Cisplatin; Clinic; Clinical; Condition; Data; Deoxyglucose; Doctor of Philosophy; Doxorubicin; Enzymes; Glycolysis; Glycolysis Inhibition; Goals; Grant; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Lead; Link; Mannose; Mannose-6-Phosphate Isomerase; Mediating; Metabolic Pathway; Metabolism; Molecular Profiling; Multiple Myeloma; Necrosis; Normal Cell; Numbers; Oxidative Phosphorylation; Oxygen; Oxygen measurement, partial pressure, arterial; Patients; Phase I Clinical Trials; Pimonidazole; Population; Positron-Emission Tomography; Production; Proteins; Protocols documentation; Public Health; Publishing; RNA Interference; Research Personnel; Resistance; Solid Neoplasm; Source; Standards of Weights and Measures; System; Testing; Toxic effect; Transcriptional Activation; Treatment Efficacy; Up-Regulation; Viral; Xenograft procedure; analog; base; cell type; chemotherapeutic agent; chemotherapy; glucose analog; glycosylation; hypoxia inducible factor 1; improved; in vitro Model; in vivo; inhibitor/antagonist; killings; neoplastic cell; programs; research study; resistance mechanism; response; small hairpin RNA; stem; sugar; tumor; tumor xenograft

DESCRIPTION (provided by applicant): A fundamental difference in sugar metabolism exists between slow-growing tumor cells found in the hypoxic regions of most solid tumors and the majority of normal cells in the body, which are under oxygen. Hypoxic cells rely solely on glycolysis for energy production, whereas cells under normal oxygen tension can metabolize other carbon sources through oxidative phosphorylation. This creates a natural window of selectivity that can be exploited for therapy by using inhibitors of glycolysis. Based on our in vitro and in vivo results, a Phase I clinical trial was recently initiated to test the hypothesis that the glycolytic inhibitor, 2-deoxyglucose (2-DG), which targets the most resistant cell population found in solid tumors, slowly-growing hypoxic cells, will raise the efficacy of treatment when combined with standard chemotherapy which targets the rapidly-dividing aerobic tumor cells. The direction for the continuation of this competitive renewal grant stems from three recent findings: The first is that the glucose analog, 2-fluro-deoxyglucose (2-FG), which is used to locate and identify tumors in patients by PET scan, has been found to be 3x more potent than 2-DG in inhibiting glycolysis and killing hypoxic tumor cells in our in vitro models. Thus, Aim #1 is directed at determining whether 2-FG has better activity than 2-DG in killing hypoxic cells in vivo. The second finding is that the ubiquitous hypoxia-inducible factor (HIF) mediates resistance to glycolytic inhibitors in hypoxic tumor cells. Results from Aim #1 will be combined with in vitro experiments in Aim #2, which are geared toward understanding how hypoxic tumor cells become resistant to glycolytic inhibitors thru up-regulation HIF. The third recent finding is that a select number of tumor cell types growing in the presence of oxygen are killed by 2-DG but not by 2-FG. Based on data from the 1970's in which 2-DG was shown to interfere with N-linked glycosylation of viral coats, it appears that the toxicity we find in these select tumor cells with 2-DG is due to the same mechanism (as opposed to inhibition of glycolysis) which forms the focus of Aim #3. Thus, the long-term goals of this proposal, which are directly relevant to public health are the following: (1) To generate data that will eventually lead to the use of 2-FG as a more potent inhibitor of glycolysis in the clinic; (2) To improve the efficacy of glycolytic inhibitors in patients by combining them with anti-HIF agents; and (3) To provide a rational basis for the clinical use of 2-DG as a single agent to kill both aerobic (via interference with glycosylation) and hypoxic (via blockage of glycolysis) cell populations in select tumor cell types that are identified in vitro to be sensitive to this sugar analog in the presence of oxygen.

描述（由申请人提供）：在大多数实体瘤的缺氧区域中发现的缓慢生长的肿瘤细胞与体内大多数处于氧气下的正常细胞之间存在糖代谢的根本差异。缺氧细胞仅依靠糖酵解来产生能量，而正常氧张力下的细胞可以通过氧化磷酸化代谢其他碳源。这创造了一个自然的选择性窗口，可以利用糖酵解抑制剂进行治疗。根据我们的体外和体内结果，最近启动了一项 I 期临床试验，以测试以下假设：糖酵解抑制剂 2-脱氧葡萄糖 (2-DG) 靶向实体瘤中最耐药的细胞群（缓慢生长的缺氧细胞），与靶向快速分裂的需氧肿瘤细胞的标准化疗相结合，将提高治疗效果。继续这项竞争性更新拨款的方向源于最近的三项发现：第一个是，在我们的体外模型中，用于通过 PET 扫描定位和识别患者肿瘤的葡萄糖类似物 2-氟脱氧葡萄糖 (2-FG) 在抑制糖酵解和杀死缺氧肿瘤细胞方面被发现比 2-DG 更有效 3 倍。因此，目标#1旨在确定2-FG在体内杀死缺氧细胞方面是否比2-DG具有更好的活性。第二个发现是，普遍存在的缺氧诱导因子（HIF）介导缺氧肿瘤细胞对糖酵解抑制剂的抵抗力。目标#1 的结果将与目标#2 的体外实验相结合，旨在了解缺氧肿瘤细胞如何通过上调 HIF 对糖酵解抑制剂产生耐药性。最近的第三个发现是，在氧气存在下生长的特定数量的肿瘤细胞类型会被 2-DG 杀死，但不会被 2-FG 杀死。根据 1970 年代的数据，其中 2-DG 被证明会干扰病毒外壳的 N 连接糖基化，看来我们在这些具有 2-DG 的选定肿瘤细胞中发现的毒性是由于相同的机制（而不是抑制糖酵解），这形成了目标 #3 的焦点。因此，该提案与公共健康直接相关的长期目标如下：（1）生成数据，最终导致在临床上使用2-FG作为更有效的糖酵解抑制剂； (2)通过与抗HIF药物联合使用，提高糖酵解抑制剂对患者的疗效； (3) 为临床使用 2-DG 作为单一药物杀死体外确定的在有氧条件下对这种糖类似物敏感的选定肿瘤细胞类型中的需氧（通过干扰糖基化）和缺氧（通过阻止糖酵解）细胞群提供合理的基础。