Role of tRXRalpha in pancreatic cancer development and therapy

描述(申请人提供)：胰腺癌是一种毁灭性的疾病。它在西方国家与癌症相关的死亡中排名第四。美国癌症协会在其2012年的《癌症事实与数字》报告中估计，今年美国将新增43,920例胰腺癌病例。胰腺癌的治疗选择仍然有限，治疗晚期胰腺癌的临床试验并没有产生太多令人兴奋的结果。因此，迫切需要发现和开发新的有效药物。要做到这一点，需要更好地了解胰腺癌的生物学， 新靶标的识别和新靶标作用机制的研究。维甲酸X受体？，RXR？，是核受体家族的一员，在包括肿瘤发生在内的许多生物学过程中起着重要的调控作用。RXR的表达和功能发生了变化？塔格列汀与许多癌症疾病有关，如乳腺癌、前列腺癌和肺癌，是一种针对RXR？的药物，已被FDA批准用于治疗皮肤T细胞淋巴瘤。最近我们发现了一个N-终端截断的RXR？(tRXR？)RXR？蛋白水解性裂解？在癌细胞中与胞浆中的PI3K相互作用，介导肿瘤坏死因子？以及非类固醇抗炎药(NSAID)舒林酸是否能与tRXR结合？调节tRXR？介导的肿瘤坏死因子？信号通路(癌细胞17,560,2010)。有趣的是，之前的一项研究表明，tRXR？在13例胰腺导管腺癌患者所建立的所有细胞系中均有高表达。然而，tRXR的作用是什么？在胰腺癌细胞的生长和耐药性尚不清楚。因此我们假设tRXR？在胰腺癌的发生发展和胰腺癌细胞对化疗的耐药性中起着关键作用，而tRXR？是治疗胰腺癌的潜在靶点。在这项初步研究的提案中，我们将通过实现以下具体目标来解决这些假设：(1)研究tRXR的作用？促进胰腺癌细胞生长和耐药；以及(2)鉴定tRXR？药物靶向的表面结合部位。我们的应用程序，它建议确定tRXR的角色？在促进胰腺癌细胞生长和耐药性以及验证新的药物靶点方面，具有探索性和新颖性。该项目有望产生新的信息，为未来广泛的tRXR？致癌潜能的机制研究奠定基础。通过R01资助机制发现治疗胰腺癌的药物。

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease. It ranks the fourth cause in cancer-related death in western countries. In its 2012 "Cancer Facts & Figures" report, American Cancer Society estimated that 43,920 new cases of pancreatic cancer would occur in the US this year. The treatment options for pancreatic cancer remain limited and clinical trials of therapies have not generated much exciting outcome in advanced pancreatic cancer. Thus, there is a strong and urgent need to discover and develop new and effective drugs. To do so, it requires a better understanding of the pancreatic cancer biology, the identification of novel targets and the investigation of the mechanisms of actions of the new targets. Retinoid X receptor-?, RXR?, is a member of the nuclear receptor family and plays an important role in the control of many biological processes including carcinogenesis. Altered expression and function of RXR? is implicated in many cancer diseases such as breast, prostate and lung cancers and a RXR?-targeted drug, Targretin was approved by FDA for treating cutaneous T-cell lymphoma. Recently we discovered that an N-terminally-truncated RXR? (tRXR?) resulted from proteolytic cleavage of RXR? in cancer cells interacted with PI3K in the cytoplasm to mediate the TNF? signaling and that the nonsteroidal anti-inflammatory drug (NSAID) Sulindac could bind to tRXR? to regulate tRXR?-mediated TNF? signaling pathways (Cancer Cell 17, 560, 2010). Interestingly, a previous study showed that tRXR? was highly produced in all cell lines established from 13 patients with pancreatic ductal adenocarcinoma. However, the role of tRXR? in the pancreatic cancer cell growth and drug resistance is unknown. Therefore we hypothesize that tRXR? plays a critical role in the development of pancreatic cancer and the resistance of pancreatic cancer cells to chemotherapy and that tRXR? is a potential target for treating pancreatic cancer. In this proposal of pilot studies we will address these hypotheses by carrying out the following Specific Aims: (1) To study the role of tRXR? in promoting pancreatic cancer cell growth and drug resistance; and (2) To identify the tRXR? surface binding site for drug targeting. Our application, which proposes to determine the role of tRXR? in promoting pancreatic cancer cell growth and drug resistance and to validate a novel drug target, is exploratory and novel. The project is expected to generate new information to lay the foundation for future extensive mechanistic study of the oncogenical potential of tRXR? and drug discovery for pancreatic cancer therapy through R01 funding mechanism.