Project 2: Chemoprevention of pancreatic cancer with lipid-lowering and antidiabetic agents

项目2：降脂和抗糖尿病药物化学预防胰腺癌

• 批准号: 10398846
• 负责人: JUAN ENRIQUE ROZENGURT
• 金额: $ 23.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398846
• 关键词: Acinus organ component; Adipose tissue; Anchorage-Independent Growth; Antidiabetic Drugs; Attenuated; Biological Availability; CXCL5 gene; Calories; Cancer Etiology; Cardiovascular Diseases; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Cholesterol; Chronic; Chronic Disease; Clinical; DNA biosynthesis; Development; Diet; Dose; Duct (organ) structure; Epidermal Growth Factor Receptor; Family; Fatty acid glycerol esters; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Growth; Growth Factor; Human; Hyperinsulinism; Inflammation; Insulin; Insulin Resistance; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; KRAS2 gene; KRASG12D; Knowledge; Lesion; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic Diseases; Metaplasia; Metformin; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Nutrient; Obesity; Obesity associated cancer; Oral Administration; Organoids; Outcome; Outcome Study; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Peripheral; Pharmaceutical Preparations; Prevention; Receptor Signaling; Research; Risk; Signal Pathway; Signal Transduction; Simvastatin; Site; Survival Rate; System; Testing; Transcription Coactivator; Translations; United States Food and Drug Administration; atorvastatin; cerivastatin; clinically significant; combinatorial; connective tissue growth factor; design; diet-induced obesity; dietary control; epidemiology study; human disease; in vivo; insulin signaling; interest; lipophilicity; mouse model; neoplastic; novel; obesity genetics; obesogenic; pancreas development; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pre-clinical; preclinical study; prevent; programs; protein expression; rho; sensor; therapeutic development; tumor

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human diseases. The focus of research, which had been placed mostly on development of therapeutic agents, has shifted gradually towards its prevention. In this context, many studies have linked obesity and long-standing type-2 diabetes mellitus with PDAC development. These metabolic diseases are characterized by peripheral insulin resistance, hyperinsulinemia, increased IGF-1 and chronic inflammation. Previously, crosstalk mechanisms between insulin/IGF-1 receptors, G protein-coupled receptor (GPCR) and EGF receptor (EGFR) signaling systems have been identified that potently stimulate proliferation of PDAC cells harboring a KRAS mutations. Mitogenic crosstalk depended on the function of mTORC1, ERK and PKD and opposed by AMPK, a target for the antidiabetic agent metformin. The identification of the key downstream targets of this signaling network is of fundamental significance and major translational interest. The YAP/TAZ transcriptional co-activators are emerging as points of integration in the action of KRAS, GPCRs and AMPK, all signaling pathways highly relevant in PDAC. New preliminary studies demonstrate that YAP/TAZ activation is a crucial point of convergence in the crosstalk between GPCR and insulin signaling in PDAC cells. Importantly, lipid-lowering drugs of the statin family potently blocked YAP/TAZ activity, including YAP/TAZ/TEAD-regulated genes, such as CTGF, Cyr61 and NUAK2. Lipophilic statins, including cerivastatin, simvastatin and atorvastatin, strikingly inhibited colony formation of human and mouse PDAC cells. Statins inhibited PDAC colony formation acting synergistically with metformin. Further preliminary results in vivo show that oral administration of simvastatin attenuated the loss of intact acini and the development of pre-neoplastic lesions in the pancreas promoted by an obesogenic diet in conditional KrasG12D (KC) mice. Accordingly, the central hypothesis to be explored in Project 2 of this P01 is that the well tolerated cholesterol-lowering drugs of the statin family inhibit obesity-induced promotion of PDAC via inhibition of PKD/YAP/TAZ. The Specific Aims of Project 2 have been designed to investigate important gaps in current knowledge: 1) Characterize the chemopreventive effects of statins on the progression of PanINs and development of PDAC using the conditional KrasG12D model (KC mice) subjected to control or diet-induced obesity (DIO) and in KC mice carrying a homozygous deletion of the ob gene. 2) Identify a novel molecular mechanism by which statins inhibit YAP/TEAD signaling in mouse and human pancreatic cells. 3) Characterize the inhibitory effect of a low-dose combination of statin and metformin on the development of PDAC: a novel chemopreventive strategy. The studies proposed in Project 2 of this P01 will provide mechanisms and rationale for novel chemo-preventive strategies in obesity-related PDAC. Since statins and metformin are widely used Food and Drug Administration (FDA)-approved drugs, the mechanistic and preclinical studies proposed have the potential for rapid translation to PDAC and other obesity-associated cancers.

项目摘要 胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）是人类最致命的疾病之一。研究的重点， 主要放在治疗药物的开发上，已经逐渐转向其 预防在这种情况下，许多研究将肥胖和长期存在的2型糖尿病与糖尿病联系起来， PDAC开发。这些代谢性疾病的特征在于外周胰岛素抵抗， 高胰岛素血症、增加的IGF-1和慢性炎症。以前， 胰岛素/IGF-1受体、G蛋白偶联受体（GPCR）和EGF受体（EGFR）信号传导系统已经 已经鉴定出其有效地刺激具有KRAS突变的PDAC细胞的增殖。丝分裂 串扰依赖于mTORC 1，ERK和PKD的功能，并由AMPK对抗，AMPK是细胞凋亡的靶点。 抗糖尿病药二甲双胍。该信令网络的关键下游目标的识别是 重要意义和重大翻译意义。雅普/TAZ转录共激活因子是 在KRAS、GPCR和AMPK的作用中作为整合点出现，所有信号通路都高度依赖于 与PDAC有关。新的初步研究表明，雅普/TAZ激活是一个关键点， 在PDAC细胞中GPCR和胰岛素信号传导之间的串扰的收敛。重要的是，降脂 他汀类药物可有效阻断雅普/TAZ活性，包括雅普/TAZ/TEAD调节基因，如 CTGF、Cyr 61和NUAK 2。亲脂性他汀类药物，包括西立伐他汀、辛伐他汀和阿托伐他汀， 抑制人和小鼠PDAC细胞的集落形成。他汀类药物抑制PDAC集落形成， 与二甲双胍协同作用。进一步的体内初步结果表明，口服辛伐他汀 减轻胰腺中完整腺泡的丧失和肿瘤前病变的发展， 条件性KrasG 12 D（KC）小鼠的致肥胖饮食。因此，本文要探讨的中心假设 本P01的项目2是耐受性良好的他汀类降胆固醇药物抑制肥胖诱导的 通过抑制PKD/雅普/TAZ促进PDAC。项目2的具体目标是 调查当前知识的重要空白：1）表征他汀类药物对肿瘤的化学预防作用， PanIN的进展和PDAC的发展，使用条件性KrasG 12 D模型（KC小鼠）， 对照或饮食诱导的肥胖症（DIO）和携带ob基因纯合缺失的KC小鼠。2)识别 他汀类药物抑制小鼠和人胰腺细胞中雅普/TEAD信号传导的新分子机制。 3)表征他汀类药物和二甲双胍的低剂量组合对以下发展的抑制作用： PDAC：一种新的化学预防策略。本P01项目2中提出的研究将提供机制 以及肥胖相关PDAC的新型化学预防策略的基本原理。由于他汀类药物和二甲双胍是 广泛使用的食品和药物管理局（FDA）批准的药物，机制和临床前研究 提出的具有快速转化为PDAC和其他肥胖相关癌症的潜力。