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.

项目概要 胰腺导管腺癌（PDAC）是人类最致命的疾病之一。研究重点， 过去主要致力于治疗药物的开发，现在已逐渐转向其 预防。在此背景下，许多研究将肥胖和长期 2 型糖尿病与 PDAC 开发。这些代谢性疾病的特点是外周胰岛素抵抗， 高胰岛素血症、IGF-1 增加和慢性炎症。以前，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 已被鉴定可有效刺激携带 KRAS 突变的 PDAC 细胞的增殖。促有丝分裂 串扰取决于 mTORC1、ERK 和 PKD 的功能，并受到 AMPK 的反对，AMPK 是 抗糖尿病药二甲双胍。该信令网络关键下游目标的识别是 具有根本意义和重大转化意义。 YAP/TAZ 转录共激活因子是 作为 KRAS、GPCR 和 AMPK 作用中的整合点，所有信号通路都高度 与 PDAC 相关。新的初步研究表明 YAP/TAZ 激活是 PDAC 细胞中 GPCR 和胰岛素信号传导之间的串扰趋于一致。重要的是降脂 他汀类药物可有效阻断 YAP/TAZ 活性，包括 YAP/TAZ/TEAD 调节基因，例如 如 CTGF、Cyr61 和 NUAK2。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，引人注目 抑制人和小鼠 PDAC 细胞集落形成。他汀类药物抑制 PDAC 集落形成 与二甲双胍有协同作用。进一步的体内初步结果表明口服辛伐他汀 减轻了胰腺中完整腺泡的丧失和肿瘤前病变的发展 条件性 KrasG12D (KC) 小鼠的致肥饮食。因此，本文要探讨的中心假设 本P01的项目2是他汀类药物家族的耐受性良好的降胆固醇药物抑制肥胖引起的 通过抑制 PKD/YAP/TAZ 促进 PDAC。项目 2 的具体目标旨在 调查当前知识中的重要差距：1）描述他汀类药物对 使用条件 KrasG12D 模型（KC 小鼠）进行 PanIN 的进展和 PDAC 的发育 对照或饮食诱导的肥胖 (DIO) 以及携带 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类胰腺细胞中 YAP/TEAD 信号传导的新分子机制。 3) 表征他汀类药物和二甲双胍低剂量组合对以下疾病发展的抑制作用 PDAC：一种新颖的化学预防策略。本 P01 项目 2 中提出的研究将提供机制 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 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 提议有可能快速转化为 PDAC 和其他与肥胖相关的癌症。