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

描述（由申请人提供）：在大多数实体瘤的缺氧区域中发现的生长缓慢的肿瘤细胞与体内处于氧气下的大多数正常细胞之间存在糖代谢的根本差异。低氧细胞仅仅依靠糖酵解来产生能量，而在正常氧张力下的细胞可以通过氧化磷酸化代谢其他碳源。这创造了一个天然的选择性窗口，可以通过使用糖酵解抑制剂用于治疗。基于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），其靶向实体瘤中发现的最具抗性的细胞群，缓慢生长的缺氧细胞，当与靶向快速分裂的需氧肿瘤细胞的标准化疗结合时，将提高治疗的疗效。继续这种竞争性更新资助的方向源于三个最近的发现：第一个是葡萄糖类似物，2-氟脱氧葡萄糖（2-FG），用于通过PET扫描定位和识别患者中的肿瘤，在我们的体外模型中，发现在抑制糖酵解和杀死缺氧肿瘤细胞方面比2-DG强3倍。因此，目的#1旨在确定2-FG在体内杀死缺氧细胞方面是否具有比2-DG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抗性。目标1的结果将与目标2的体外实验相结合，这些实验旨在了解低氧肿瘤细胞如何通过上调HIF对糖酵解抑制剂产生抗性。最近的第三个发现是，在氧气存在下生长的选定数量的肿瘤细胞类型被2-DG杀死，但不被2-FG杀死。基于20世纪70年代的数据，其中2-DG被证明干扰病毒外壳的N-连接糖基化，我们在这些选择的肿瘤细胞中发现的2-DG的毒性似乎是由于形成目标#3的焦点的相同机制（与抑制糖酵解相反）。因此，该提案的长期目标与公共卫生直接相关，具体如下：（1）生成最终将导致在临床中使用2-FG作为更有效的糖酵解抑制剂的数据;（2）通过将糖酵解抑制剂与抗HIF药物联合使用，提高糖酵解抑制剂在患者中的疗效;为临床上2-DG单药杀灭需氧菌和大肠杆菌提供了合理的依据（通过干扰糖基化）和缺氧（通过阻断糖酵解）选择的肿瘤细胞类型中的细胞群，所述肿瘤细胞类型在体外被鉴定为在氧存在下对这种糖类似物敏感。

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.