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：
8373906
负责人：
JUAN ENRIQUE ROZENGURT
金额：
$ 20.83万
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：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8373906
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 Engineering Epidemiologic Studies Epidermal Growth Factor Receptor Fatty acid glycerol esters G-Protein-Coupled Receptors 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

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 Engineering Epidemiologic Studies Epidermal Growth Factor Receptor Fatty acid glycerol esters G-Protein-Coupled Receptors 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

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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）是最致命的人类疾病之一。近年来，研究重点主要放在治疗剂的开发上，已经改变了逐渐接近预防。在这种情况下，许多流行病学研究已将肥胖，代谢联系起来综合征和长期存在的2型糖尿病（T2DM），患有PDAC和PDAC的风险增加其他临床上侵略性的癌症。我们的初步研究确定了串扰机制胰岛素/IGF-1受体，G蛋白偶联受体（GPCR）和EGF受体（EGFR）信号传导系统这可能刺激人PDAC中的DNA合成，细胞增殖和非锚固的生长细胞。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）的靶标。 Biguanide二甲双胍，一种广泛的处方药 T2DM的处理，对MTORCI进行负调节。进一步的初步研究表明二甲双胍潜在地阻断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PDAC细胞在Xenographogroticon小鼠模型中的生长。最近的流行病学研究将二甲双胍的给药与T2DM患者的PDAC风险降低有关，而给药胰岛素或胰岛素促分泌物的作用似乎会执行相反的效果。基于所有这些研究，我们定位该二甲双胍通过抑制营养，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。因此，我们的核心假设是耐受性良好且廉价的反抗糖尿病药物二甲双胍抑制饮食诱导的胰腺癌促进。检验此中心假设我们建议追求以下特定目的：1）确定二甲双胍抑制的机制一组胰腺细胞中的有丝分裂信号传导，代表导管进展的体外模型胰腺细胞到PDAC； 2）表征二甲双胍对进展的化学预防作用使用有条件的克拉斯'^€模型进行标准或高脂肪，高卡路里饮食（HFCD）的panlns。 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。在模仿的细胞培养系统中将阐述不足的机制胰腺癌发展的不同阶段。最先进的基因工程动物模型将用于检验该项目的中心假设。相关性（请参阅说明）：我们预计提供了我们的假设，即二甲双胍可显着延迟或阻止肿瘤促进高脂肪高热量饮食（HFCD）的影响。由于二甲双胍是FDA批准的药物治疗2型糖尿病，我们的研究将提供科学的基本原理胰腺癌的化学预防并阐明其机制。我们的结果也可以转移到其他与肥胖相关的癌症，甚至是非恶性慢性疾病。