Chemoprevention of pancreatic cancer witli antidiabetic agents

胰腺导管腺癌（Pancreatic ductal adenocarcinoma，PDAC）是人类最致命的疾病之一。近年来 研究的重点，主要是放在开发治疗剂，已经转移 逐步走向预防。在这种背景下，许多流行病学研究将肥胖、代谢性疾病和肥胖症联系起来。 综合征和长期存在的2型糖尿病（T2 DM），发生PDAC的风险增加， 其他临床侵袭性癌症。我们的初步研究确定了串扰机制之间 胰岛素/IGF-1受体、G蛋白偶联受体（GPCR）和EGF受体（EGFR）信号系统 其有效地刺激人PDAC中DNA合成、细胞增殖和锚定非依赖性生长 细胞这些信号系统之间的促有丝分裂串扰依赖于哺乳动物细胞的功能， 雷帕霉素（mTOR）复合物1（mTORCI）靶点。双胍二甲双胍，一种广泛用于 治疗T2 DM，负调节mTORCI。进一步的初步研究表明，二甲双胍 在体外有效地阻断PDAC细胞中的促有丝分裂信号传导，并且其给药（口服或口服） 腹膜内）抑制PDAC细胞在异种移植小鼠模型中的生长。最近的流行病学 在T2 DM患者中，二甲双胍给药与PDAC风险降低相关的研究， 胰岛素或胰岛素促分泌素似乎发挥相反的作用。基于所有这些研究，我们 二甲双胍通过抑制营养、能量和生长因子， 传感器mTORCI。因此，我们的中心假设是，耐受性好且廉价的抗- 糖尿病药物二甲双胍抑制饮食诱导的胰腺癌的促进作用。为了验证这个核心假设 我们建议追求以下具体目标：1）确定二甲双胍抑制 一组胰腺细胞中的促有丝分裂信号传导，代表导管癌进展的体外模型 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模型进行标准或高脂肪、高热量饮食（HFCD）的PanIN。 3)描述二甲双胍和雷帕霉素对PDAC进展的影响：一种新的组合药物， 化学预防策略将在模拟细胞培养系统的细胞培养系统中剖析不可理解的机制。 胰腺癌发展的不同阶段。最先进的基因工程动物模型将 用于检验本项目的中心假设。 相关性（参见说明）： 我们期待证明我们的假设，即二甲双胍显著延迟或阻止促肿瘤细胞增殖。 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理由， 胰腺癌的化学预防，并阐明其机制。我们的研究结果也可以转移到 其他与肥胖有关的癌症，甚至非恶性慢性疾病。

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.