Chemoprevention of pancreatic cancer witli antidiabetic agents

胰腺导管腺癌（PDAC）是人类最致命的疾病之一。近年来， 研究重点主要集中在治疗药物的开发上，现在已经转移 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 综合征和长期存在的 2 型糖尿病 (T2DM) 会增加患 PDAC 的风险 其他临床侵袭性癌症。我们的初步研究确定了之间的串扰机制 胰岛素/IGF-1 受体、G 蛋白偶联受体 (GPCR) 和 EGF 受体 (EGFR) 信号系统 有效刺激人类 PDAC 中的 DNA 合成、细胞增殖和贴壁独立生长 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。双胍类二甲双胍是一种广泛用于治疗的处方药 T2DM 的治疗，负调节 mTORCI。进一步的初步研究表明二甲双胍 在体外有效阻断 PDAC 细胞中的有丝分裂信号传导，并且其给药（口服或 腹膜内）抑制异种移植小鼠模型中 PDAC 细胞的生长。近期流行病学 研究表明，服用二甲双胍可降低 T2DM 患者发生 PDAC 的风险 胰岛素或胰岛素促分泌剂的使用似乎发挥相反的作用。基于所有这些研究，我们假设 二甲双胍通过抑制营养物、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，我们的中心假设是，耐受性良好且廉价的抗 糖尿病药物二甲双胍可抑制饮食诱导的胰腺癌进展。为了检验这个中心假设 我们建议追求以下具体目标： 1) 确定二甲双胍抑制的机制 一组胰腺细胞中的促有丝分裂信号代表导管进展的体外模型 胰腺细胞至 PDAC； 2) 表征二甲双胍对疾病进展的化学预防作用 PanlNs 使用条件 Kras 模型进行标准或高脂肪、高热量饮食 (HFCD)。 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。将在模仿细胞培养系统的基础机制中进行剖析 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（参见说明）： 我们期望证明我们的假设，即二甲双胍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，广泛用于 2 型糖尿病的治疗，我们的研究将为它的使用提供科学依据 胰腺癌的化学预防并阐明其机制。我们的成果也可以转移到 其他与肥胖相关的癌症，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.