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

描述(申请人提供)：在大多数实体肿瘤的缺氧区发现的缓慢生长的肿瘤细胞与体内大多数处于氧气中的正常细胞在糖代谢方面存在根本差异。低氧细胞完全依赖糖酵解来产生能量，而正常氧分压下的细胞可以通过氧化磷酸化来代谢其他碳源。这创造了一个自然的选择性窗口，可以通过使用糖酵解抑制剂进行治疗。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)针对实体瘤中发现的最具耐药性的细胞群，缓慢生长的低氧细胞，当与针对快速分裂的有氧肿瘤细胞的标准化疗相结合时，将提高治疗效果。继续这项竞争性续期赠款的方向来自三个最近的发现：第一，在我们的体外模型中，用于通过PET扫描来定位和识别患者肿瘤的葡萄糖类似物2-氟尿脱氧葡萄糖(2-FG)被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，目标#1旨在确定2-FG在体内是否比2-DG具有更好的杀灭缺氧细胞的活性。第二个发现是，无处不在的缺氧诱导因子(HIF)介导了缺氧性肿瘤细胞对糖酵解抑制剂的抵抗。AIM#1的结果将与AIM#2的体外实验相结合，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药性。最近的第三个发现是，在氧气存在下生长的一些肿瘤细胞类型可以被2-DG杀死，但不能被2-FG杀死。基于20世纪70年代S的数据，其中2-DG被证明干扰病毒衣壳的N-连接糖基化，我们在这些使用2-DG的精选肿瘤细胞中发现的毒性似乎是由于形成目标3的焦点的相同机制(相对于抑制糖酵解)。因此，这项建议的长期目标如下：(1)产生最终将导致在临床上使用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药物联合使用来提高患者的疗效；以及(3)为临床使用2-DG作为单一药物在选定的肿瘤细胞类型中杀灭需氧细胞(通过干扰糖基化)和低氧细胞(通过阻断糖酵解)提供合理的基础；这些肿瘤细胞在体外被鉴定为在有氧的情况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.