A new energy restriction mimetic that targets pancreatic cancer

描述（由申请人提供）：胰腺癌是所有癌症中最致命的癌症之一，只有6%的患者存活超过5年。众所周知，卡路里 限制是抑制包括胰腺癌在内的癌症的有力干预。最近的研究表明，能量限制模拟物（ERM）的使用可以获得热量限制的代谢反应特征。通过抑制糖酵解的ERM靶向葡萄糖代谢与胰腺癌非常相关，因为90%的这些癌症在Kras基因中具有突变，这依赖于糖酵解生存。新的ERM，OSU-CG 5降低胰腺癌细胞的存活率并诱导细胞凋亡，这与细胞存活所必需的RNA结合蛋白HuR降低有关。我们提出，ERM OSU-CG 5降低HuR表达，导致发病率降低和存活率提高，这具有临床重要性，因为沉默HuR已显示使胰腺癌细胞对DNA损伤化疗剂敏感（12 d）。此外，我们假设OSU-CG 5通过下调HuR提高胰腺癌细胞对DNA损伤剂的敏感性。以下目标将解决这一假设。1.确定ERM OSU-CG 5在延迟KrasG 12 D; Trp 53 R172 H;Pdx-1Cre小鼠中胰腺肿瘤的发展和进展以及改善存活率方面的有效性。我们将评估OSU-CG 5对KrasG 12 D; Trp 53 R172 H;Pdx-1Cre小鼠胰腺肿瘤发病率和存活率的影响。为了探索OSU-CG 5潜在抗肿瘤作用的机制，我们将测量肿瘤组织中葡萄糖、胰岛素或IGF-1的循环浓度、增殖和凋亡。2.通过测定以下指标，研究KPC、Mia Paca和Panc 1胰腺癌细胞和KrasG 12 D; Trp 53 R172 H;Pdx-1Cre小鼠肿瘤中响应OSU-CG 5介导细胞存活减少和诱导细胞凋亡的机制：（a）HuR和Glut 1表达（B）OSU-CG 5降低HuR蛋白的机制（c）细胞死亡的类型，（d）胰腺癌细胞中细胞存活率的降低和细胞凋亡的诱导是否由HuR介导，和（e）OSU-CG 5是否将改善对DNA损伤剂的敏感性。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most fatal of all cancers with only 6% of the patients living longer than 5 years. It is very well known that calorie restriction is a powerful intervention to suppress cancer including pancreatic cancer. Recent studies have shown that metabolic responses characteristic of calorie restriction can be obtained with the use of energy restriction mimetics (ERM). Targeting glucose metabolism by ERM that inhibit glycolysis is very relevant to pancreatic cancer because 90% of these cancers have a mutation in the Kras gene, which is dependent on glycolysis for survival. The new ERM, OSU-CG5 decreases survival and induces apoptosis in pancreatic cancer cells in association with decreased HuR, an RNA-binding protein necessary for cell survival. We propose that the ERM OSU-CG5 decreases HuR expression resulting in reduced incidence and improved survival, which has clinical importance because silencing HuR has been shown to sensitize pancreatic cancer cells to DNA damaging chemotherapeutics (12d). Additionally, we hypothesize that OSU-CG5 improves sensitivity of pancreatic cancer cells to DNA damaging agents through downregulation of HuR. The following aims will address this hypothesis. 1. To determine the effectiveness of the ERM OSU-CG5 in delaying the development and progression of pancreatic tumors and improving survival in KrasG12D; Trp53R172H;Pdx-1Cre mice. We will evaluate the effect of OSU-CG5 on incidence of pancreatic tumors and survival of KrasG12D; Trp53R172H;Pdx-1Cre mice. To explore the mechanisms for the potential anti-tumor effect of OSU-CG5, we will measure circulating concentrations of glucose, insulin, or IGF-1, proliferation and apoptosis in tumor tissue. 2. To investigate the mechanisms mediating the decreased cell survival and induction of apoptosis in response to OSU-CG5 in KPC, Mia Paca and Panc1 pancreatic cancer cells and tumors from KrasG12D; Trp53R172H;Pdx-1Cre mice by determining: (a) HuR and Glut1 expression (b) the mechanism by which OSU-CG5 decreases HuR protein (c) the type of cell death, (d) whether the decrease in cell survival and induction of apoptosis in pancreatic cancer cells is mediated by HuR, and (e) whether OSU-CG5 will improve sensitivity to DNA damaging agents.