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发现的生长缓慢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着糖代谢的根本差异。缺氧细胞仅依靠糖酵解产生能量，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。基于我们在体外和体内的结果，我们最近启动了一项I期临床试验，以验证糖酵解抑制剂2-脱氧葡萄糖（2-DG）的假设，该抑制剂针对实体肿瘤中最耐药的细胞群，缓慢生长的缺氧细胞，当与针对快速分裂的需氧肿瘤细胞的标准化疗联合使用时，将提高治疗效果。这项竞争性更新拨款的持续方向源于最近的三个发现：首先，在我们的体外模型中，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的效力是2-DG的3倍，2-氟脱氧葡萄糖用于通过PET扫描定位和识别患者的肿瘤。因此，Aim #1旨在确定2-FG是否比2-DG在体内杀死缺氧细胞方面具有更好的活性。第二个发现是无处不在的缺氧诱导因子（HIF）介导了缺氧肿瘤细胞对糖酵解抑制剂的抗性。Aim #1的结果将与Aim #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被2-DG杀死，而不是2-FG。根据20世纪70年代的数据，2-DG被证明会干扰病毒外衣的n -链糖基化，我们在这些选择的肿瘤细胞中发现的2-DG的毒性似乎是由于相同的机制（与糖酵解的抑制相反），这是Aim #3的重点。因此，该提案的长期目标与公共卫生直接相关：(1)生成数据，最终将导致2-FG在临床中作为更有效的糖酵解抑制剂使用；(2)联合抗hif药物提高糖酵解抑制剂在患者中的疗效；(3)为临床使用2-DG作为单一药物杀死在体外鉴定对这种糖类似物在氧气存在下敏感的肿瘤细胞类型中的有氧（通过干扰糖基化）和缺氧（通过阻断糖酵解）细胞群提供合理依据。

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.