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。近几年来， 过去主要放在治疗药物开发上的研究重点已经转移 逐渐走向预防。在此背景下，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(T2 DM)，患PDAC和 其他临床侵袭性癌症。我们的初步研究确定了串扰机制 胰岛素/胰岛素样生长因子-1受体、G蛋白偶联受体和表皮生长因子受体信号系统 能有效刺激人PDAC的DNA合成、细胞增殖和非锚定生长 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)复合体的靶点1(MTORCI)。二甲双胍，一种广泛用于治疗的处方药物 治疗T2 DM，负性调节mTORCI。进一步的初步研究表明，二甲双胍 在体外有效地阻断PDAC细胞的有丝分裂信号，并且它的给药(口服或 在异种移植小鼠模型中)抑制PDAC细胞的生长。最新流行病学 在T2 DM患者服药的同时服用二甲双胍与降低PDAC风险的研究 胰岛素或胰岛素促分泌剂似乎产生了相反的效果。基于所有这些研究，我们假设 二甲双胍通过抑制营养、能量和生长因子靶向PDAC中的有丝分裂信号 传感器mTORCI。因此，我们的中心假设是，耐受性好、价格低廉的反兴奋剂 糖尿病药物二甲双胍抑制饮食诱导的胰腺癌促进作用。为了检验这一中心假设 我们建议追求以下具体目标：1)确定二甲双胍抑制的机制(S) 代表导管进展体外模型的一组胰腺细胞中的有丝分裂信号 2)研究二甲双胍对胰腺癌进展的化学预防作用。 使用条件Kras‘^模型的PanLN接受标准或高脂肪、高卡路里饮食(HFCD)。 3)研究二甲双胍和雷帕霉素对PDAC进展的影响：一个新的组合 化学预防策略。我们将剖析细胞培养系统中的未衍生机制，以模拟 胰腺癌发展的不同阶段。最先进的转基因动物模型将 被用来检验这个项目的中心假设。 相关性(请参阅说明)： 我们期待着证明我们的假设，即二甲双胍显著延缓或阻止肿瘤的促进 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 对于2型糖尿病的治疗，我们的研究将为其在 胰腺癌的化学预防并阐明其机制。我们的结果也可能被转移到 其他与肥胖相关的癌症，甚至非恶性慢性病。

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.