A new energy restriction mimetic that targets pancreatic cancer

描述(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措施。最近的研究表明，利用能量限制拟态(ERM)可以获得具有热量限制特征的代谢反应。通过ERM靶向抑制糖酵解的葡萄糖代谢与胰腺癌密切相关，因为90%的胰腺癌有依赖糖酵解生存的Kras基因突变。新的ERM OSU-CG5降低了胰腺癌细胞的存活率，并诱导了细胞的凋亡，而Hur是细胞生存所必需的一种RNA结合蛋白。我们认为ERM OSU-CG5减少Hur的表达，从而降低发病率和提高生存率，这具有临床意义，因为沉默Hur已被证明能使胰腺癌细胞对DNA损伤性化疗药物敏感(12d)。此外，我们假设OSU-CG5通过下调HUR来提高胰腺癌细胞对DNA损伤剂的敏感性。以下目标将解决这一假设。1.研究ERM OSU-CG5对KrasG12D、Trp53R172H、PDX-1Cre小鼠胰腺肿瘤的抑制作用。我们将评估OSU-CG5对KrasG12D、Trp53R172H、PDX-1Cre小鼠胰腺肿瘤发生率和存活的影响。为了探讨OSU-CG5潜在的抗肿瘤作用的机制，我们将检测循环中葡萄糖、胰岛素或IGF-1的浓度以及肿瘤组织中的增殖和凋亡。2.研究OSU-CG5对KPC、Mia Paca和Panc1胰腺癌细胞及KrasG12D、Trp53R172H、PDX-1Cre小鼠肿瘤细胞存活率降低和诱导凋亡的作用机制，通过检测：(A)Hur和Glut1的表达(B)OSU-CG5降低Hur蛋白的机制(C)细胞死亡类型；(D)OSU-CG5是否通过Hur介导胰腺癌细胞的存活和诱导凋亡；(E)OSU-CG5是否会提高对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.