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

项目总结 胰腺导管腺癌(PDAC)是人类最致命的疾病之一。研究的重点是， 曾经主要放在治疗药物开发上的，已经逐渐转向它的 预防。在这种背景下，许多研究已经将肥胖和长期存在的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升高和慢性炎症。以前，串扰机制在 胰岛素/IGF-1受体、G蛋白偶联受体(GPCR)和EGF受体(EGFR)信号系统 已被证实能有效刺激携带KRAS突变的PDAC细胞的增殖。有丝分裂 串扰依赖于mTORC1、ERK和PKD的功能，并被AMPK所反对，AMPK是 降糖剂二甲双胍。这个信令网络的关键下游目标的识别是 基本意义和主要翻译兴趣。YAP/TAZ转录共激活子是 在KRAS、GPCRs和AMPK的作用中出现整合点，所有这些信号通路都高度 与PDAC相关。新的初步研究表明，YAP/TAZ的激活是 PDAC细胞中GPCR和胰岛素信号之间的串扰收敛。重要的是，降脂 他汀类药物能有效地阻断YAP/TAZ活性，包括YAP/TAZ/TEAD调节的基因，如 CTGF、Cyr61和NUAK2。亲脂性的他汀类药物，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细胞的集落形成。他汀类药物抑制PDAC集落形成作用 与二甲双胍有协同作用。进一步的体内初步结果显示，口服辛伐他汀 减轻完整腺泡的丢失和促进胰腺癌前病变的发展 条件性KrasG12D(KC)小鼠的肥胖饮食。因此，要探索的中心假设是 这一P01的项目2是他汀类药物家族中耐受性良好的降胆固醇药物抑制肥胖诱导 通过抑制PKD/YAP/TAZ促进PDAC的表达。项目2的具体目标旨在 调查当前知识中的重要差距：1)表征他汀类药物对血管内皮细胞癌的化学预防作用 应用条件性KrasG12D模型(KC小鼠)研究PANINS的进展和PDAC的发展 对照或饮食诱导的肥胖(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YAP/TEAD信号的新分子机制。 3)表征低剂量他汀类药物和二甲双胍联合应用对血管内皮细胞癌发展的抑制作用 PDAC：一种新的化学预防策略。本P01项目2中建议的研究将提供机制 以及肥胖相关PDAC中新的化学预防策略的理论基础。因为他汀类和二甲双胍 广泛使用的食品和药物管理局(FDA)批准的药物、作用机制和临床前研究 建议有可能快速转化为PDAC和其他与肥胖相关的癌症。

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.