对于恶性程度高且非常难治的胰腺癌，寻找新靶点和新药物迫在眉睫。近期研究证明雌激素受体(ER)通路对肺癌等“非激素依赖型”肿瘤的进展起重要作用，ER可作为此类癌症内分泌治疗的新靶点。糖皮质激素(GC)可降低瘤内雌激素水平来抑制乳腺和肺肿瘤的生长，但GC内分泌治疗胰腺癌的研究尚属空白。通过前期研究和文献调研提出假设：GC通过干预雌激素代谢等作用可以内分泌治疗胰腺癌。本研究拟通过RT-PCR、免疫组化等多种方法验证ER亚型在胰腺癌中的靶点作用；在人胰腺癌细胞和病人肿瘤组织接种的两种移植瘤模型中，考察系列GCs对胰腺癌的药效和安全性，主要考察内分泌治疗相关抗癌机理；评价不同GC的药动学(PK)和药效学(PD)性质并建立PK/PD模型，通过模型仿真优化治疗方案，并初步实现GCs从体外到体内、动物到人的大致外推。课题将为胰腺癌治疗提供新靶点、新药物和合理给药方案，具有重要理论价值和广阔的应用转化前景。

Pancreatic cancer is one of the most aggressive forms of cancer, with a low mean 5-year survival rate of 3–5%, and it is the fourth leading cause of cancer-related death. Therefore, it is of great importance and urgency to find novel therapeutic targets and medications for the treatment of pancreatic cancer, and 90% of pancreatic cancer comes from pancreatic ductal adenocarcinoma (PDAC). Recently, emerging studies have found that the activation of estrogen receptor(ER) signaling pathways plays a pivotal role in the genesis and progression of several cancers, such as lung cancer and gastric cancers, which are traditionally considered as estrogen non-dependent cancers. Accordingly, blockage of estrogen signaling pathway appears to be a promising approach for these cancer treatment. It has been proven that glucocorticoids (GCs), including dexamethasone (DEX), produced significant tumor inhibition in breast cancer and non-small cell lung cancer as endocrine therapeutic agents, which is associated with induction of estrogen sulfotransferase (EST) and down-regulating the intratumoral estrogen level. However, the anti-estrogenic efficacy of GCs on PDAC, application of GCs to PDAC therapy as well as their modes of actions in tumor cells have not yet been well explored. Based on literature researches, as well as the promising outcomes of our recent preliminary studies of the inhibitory effects of GCs on the tumor growth of both SW1990 (a human PDAC cell line) xenografts and patient derived xenografts (PDX), we raised a hypothesis that the intervention of estrogen metabolism is one of the most important mechanisms in the treatment of PDAC by GCs. Our specific aims in the current research proposal accordingly are: (1) to investigate the function of ER signaling pathway in the treatment of PDAC using Elisa, real-time PCR, Western blot assay; (2) to evaluate the inhibitory effects of GCs on the proliferation of PDAC cells, and the anti-cancer effects of GCs on both xenograft models; (3) to elucidate the corresponding anti-cancer mechanisms on the basis of siRNA technique, flow cytometry analysis, immunohistochemical labelling, and so on; (4) to determine the concentrations of different GCs in both plasma and tumor tissues using LC-MS/MS methods and to evaluate their pharmacokinetic (PK) characteristics, and to establish the pharmacokinetic/pharmacodynamic (PK/PD) models of them, which would be further applied to predict and optimize dose regimens by simulations; (5) to characterize the relationship of anti-cancer effect between these two animal xenografts quantitatively and to preliminarily realize the in-vitro to in-vivo extrapolation and inter species extrapolation. It is our expectation that the results from conducting the proposed research projects could contribute greatly to: (i) finding novel therapeutic targets and medications for PDAC treatment; (ii) providing optimized regimens which may be referred to clinically. Furthermore, our future investigation will provide beneficial information to our understanding of PDAC and other adenocarcinomas, thus suggesting a broad application prospect of GCs.