Chemoprevention of pancreatic cancer witli antidiabetic agents

使用抗糖尿病药物化学预防胰腺癌

基本信息

批准号：
8561428
负责人：
JUAN ENRIQUE ROZENGURT
金额：
$ 19.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561428
关键词：
Adenocarcinoma Cell Anchorage-Independent Growth Animal Model Antidiabetic Drugs Biguanides Biological Availability Cancer Etiology Cell Culture System Cell Proliferation Cells Chemoprevention Chemopreventive Agent Chronic Disease Complex DNA biosynthesis Development Diet Disease Drug Prescriptions Duct (organ) structure Ductal Epidemiologic Studies Epidermal Growth Factor Receptor Fatty acid glycerol esters G-Protein-Coupled Receptors Genetic Engineering Growth Growth Factor Human In Vitro Incidence Instruction Insulin Insulin Resistance Insulin-Like Growth Factor I Lesion Link Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Diseases Metabolic syndrome Metformin Microcirculation Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Non-Malignant Nutrient Obesity Obesity associated cancer Outcome Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Peripheral Pharmaceutical Preparations Prevention Principal Investigator Receptor Signaling Research Risk Signal Transduction Sirolimus Site Staging Survival Rate System Testing Therapeutic Agents Translations United States Food and Drug Administration Woman Xenograft procedure analog base combinatorial human disease insulin secretagogues islet mTOR protein men mortality mouse model novel prevent receptor sensor tumor

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases. In recent years, the focus of research, which had been placed mostly on development of therapeutic agents, has shifted gradually towards its prevention. In this context, many epidemiological studies have linked obesity, metabolic syndrome and long-standing type-2 diabetes mellitus (T2DM) with increased risk for developing PDAC and other clinically aggressive cancers. Our preliminary studies identifled crosstalk mechanisms between insulin/IGF-1 receptors, G protein-coupled receptor (GPCR) and EGF receptor (EGFR) signaling systems that potently stimulate DNA synthesis, cell proliferation and anchorage-independent growth in human PDAC cells. Mitogenic crosstalk between these signaling systems depended on the function of the mammalian target of rapamycin (mTOR) complex 1 (mTORCI). The biguanide metformin, a widely prescribed drug for treatment of T2DM, negatively regulates mTORCI. Further preliminary studies demonstrate that metformin potently blocks mitogenic signaling in PDAC cells in vitro and that its administration (either orally or intraperitoneally) inhibits the growth of PDAC cells in xenograft mouse models. Recent epidemiological studies linked administration of metformin with reduced risk of PDAC in T2DM patients while administration of insulin or insulin secretagogues appears to exert the opposite effect. Based on all these studies, we posit that metformin targets mitogenic signaling in PDAC via inhibition of the nutrient, energy and growth factor sensor mTORCI. Consequently, our central hypothesis is that the well tolerated and inexpensive anti- diabetic drug metformin inhibits diet-induced promotion of pancreatic cancer. To test this central hypothesis we propose to pursue the following Specific Aims: 1) Identify the mechanism(s) by which metformin inhibits mitogenic signaling in a panel of pancreatic cells representing an vitro model of progression of ductal pancreatic cells to PDAC; 2) Characterize the chemopreventive effects of metformin on the progression of PanlNs using the conditional Kras¿'^¿ model subjected to standard or a high fat, high calorie diet (HFCD). 3) Characterize the effects of metformin and rapamycin on the progression of PDAC: a novel combinatorial chemopreventive strategy. Underiying mechanisms will be dissected in cell culture systems that mimic the different stages of pancreatic cancer development. State-of-the-art genetically engineered animal models will be utilized to test the central hypothesis of this Project. RELEVANCE (See instructions): We anticipate proving our hypothesis that metformin significantly delays or prevents the tumor-promoting effects ofthe high fat, high calorie diet (HFCD). Since metformin is a FDA-approved drug widely used in the treatment of type 2 diabetes mellitus, our studies will provide the scientiflc rationale for its use in chemoprevention of pancreatic cancer and elucidate its mechanism. Our results may also be transferable to other obesity-related cancer and even non-malignant chronic diseases.

胰腺导管腺癌（PDAC）是近年来人类最致命的疾病之一。研究重点主要集中在治疗药物的开发上，现在已经转移在此背景下，许多流行病学研究将肥胖与代谢联系起来。综合征和长期存在的 2 型糖尿病 (T2DM) 会增加患 PDAC 的风险我们的初步研究确定了其他临床侵袭性癌症之间的串扰机制。胰岛素/IGF-1 受体、G 蛋白偶联受体 (GPCR) 和 EGF 受体 (EGFR) 信号系统有效刺激人类 PDAC 的 DNA 合成、细胞增殖和贴壁独立生长这些信号系统之间的有丝分裂串扰取决于哺乳动物的功能。雷帕霉素 (mTOR) 复合物 1 (mTORCI) 的靶点双胍二甲双胍，一种广泛用于治疗的药物。进一步的初步研究表明，二甲双胍对 T2DM 具有负调节作用。在体外有效阻断 PDAC 细胞中的有丝分裂信号传导，并且其给药（口服或腹膜内）抑制异种移植小鼠模型中 PDAC 细胞的生长。研究表明，服用二甲双胍可降低 T2DM 患者发生 PDAC 的风险根据所有这些研究，我们认为胰岛素或胰岛素促分泌剂似乎会产生相反的作用。二甲双胍通过抑制营养物、能量和生长因子来靶向 PDAC 中的有丝分裂信号传导传感器 mTORCI 进行了测试，我们的中心假设是耐受性良好且廉价的抗糖尿病药物二甲双胍可抑制饮食诱导的胰腺癌的进展，以检验这一中心假设。我们建议追求以下具体目标： 1) 确定二甲双胍抑制的机制一组胰腺细胞中的促有丝分裂信号代表导管进展的体外模型胰腺细胞对 PDAC 的影响；2) 表征二甲双胍对 PDAC 进展的化学预防作用使用条件 Kras 的 PanlNs¿ '^¿模型接受标准或高脂肪、高热量饮食（HFCD）。 3) 表征二甲双胍和雷帕霉素对 PDAC 进展的影响：一种新型组合化学预防策略将在模仿细胞培养系统中进行剖析。最先进的基因工程动物模型将研究胰腺癌发展的不同阶段。用于检验该项目的中心假设。相关性（参见说明）：我们期望证明我们的假设，即二甲双胍显着延迟或阻止肿瘤促进高脂肪、高热量饮食 (HFCD) 的影响，因为二甲双胍是 FDA 批准的广泛使用的药物。 2 型糖尿病的治疗，我们的研究将为它的使用提供科学依据胰腺癌的化学预防并阐明其机制我们的结果也可能适用于。其他与肥胖相关的癌症，甚至非恶性慢性疾病。