A new energy restriction mimetic that targets pancreatic cancer

一种针对胰腺癌的新能量限制模拟物

基本信息

批准号：
9137636
负责人：
Susan Patricia Lanza-Jacoby
金额：
$ 16.97万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-04 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137636
关键词：
Address Affect Animal Model Apoptosis Caloric Restriction Cancer Patient Cell Cycle Cell Death Cell Survival Cell physiology Characteristics Clinical DNA Damage Data Development Diagnosis Disease Down-Regulation Effectiveness Energy Metabolism Genes Glucose Glucose Transporter Glycolysis Growth Health HuR protein Incidence Induction of Apoptosis Insulin Insulin-Like Growth Factor I Intervention Lead Lesion Life Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Measures Mediating Messenger RNA Metabolic Mus Mutation NIH Program Announcements Normal Cell Oncogenic Outcome Pancreas Pancreatic Ductal Adenocarcinoma Patients Pilot Projects Proliferating Prostatic Intraepithelial Neoplasias RNA-Binding Proteins Resistance SLC2A1 gene Survival Rate Testing Transgenic Mice Tumor Tissue Up-Regulation antitumor effect base chemotherapy glucose metabolism glucose transport improved inhibitor/antagonist meetings mimetics mouse model novel novel strategies pancreatic cancer cells pancreatic neoplasm protein expression response transgenic adenocarcinoma of mouse prostate tumor

项目摘要

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.

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％的患者寿命超过5岁。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，使用能量限制模拟物（ERM）可以获得卡路里限制的代谢反应的特征。通过ERM靶向抑制糖酵解的葡萄糖代谢与胰腺癌非常相关，因为这些癌症中有90％在KRAS基因中具有突变，这取决于糖酵解的生存。新的ERM，OSU-CG5降低了存活率并诱导胰腺癌细胞中的凋亡，而HUR降低了，这是细胞存活所必需的RNA结合蛋白。我们建议ERM OSU-CG5降低HUR表达，导致发病率降低和生存率提高，这具有临床重要性，因为已显示沉默的HUR被证明可以使胰腺癌细胞对DNA造成DNA损害化学治疗剂（12D）。此外，我们假设OSU-CG5通过下调HUR来提高胰腺癌细胞对DNA破坏剂的敏感性。以下目标将解决这一假设。 1。确定ERM OSU-CG5在延迟胰腺肿瘤的发育和进展方面的有效性，并提高Krasg12d的生存； TRP53R172H; PDX-1CRE小鼠。我们将评估OSU-CG5对胰腺肿瘤发生率和Krasg12d存活的影响； TRP53R172H; PDX-1CRE小鼠。为了探索OSU-CG5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。研究介导KPC，MIA PACA和PACC1胰腺癌细胞和KRASG12D肿瘤的OSU-CG5响应细胞存活和凋亡降低的机制；通过确定：（a）HUR和GLUT1表达（b）OSU-CG5降低HUR蛋白（C）细胞死亡类型，（D）pDX-1CRE的PDX-1CRE小鼠的TRP53R172H; PDX-1CRE小鼠（a）hur和glut1表达（b）降低细胞死亡类型的机制，（c）细胞存活的类型以及pan rangiative pans pans pans py nai是否会介导pans pans pans pys andA pans pligiation andA dam damigitions dans andA和（E）是否会介导OSU-cg5。