Role of tRXRalpha in pancreatic cancer development and therapy

描述（由申请人提供）：胰腺癌是一种毁灭性的疾病。它在西方国家癌症相关死亡中排名第四。在2012年的“癌症事实与数据”报告中，美国癌症协会估计今年美国将发生43，920例胰腺癌新病例。胰腺癌的治疗选择仍然有限，并且治疗的临床试验在晚期胰腺癌中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生物学， 新靶点的鉴定和新靶点作用机制的研究。维甲酸X受体-？，RXR？是核受体家族的一员，在控制包括癌发生在内的许多生物过程中起重要作用。RXR的表达和功能改变？与许多癌症疾病有关，如乳腺癌、前列腺癌和肺癌，靶向药物Targretin被FDA批准用于治疗皮肤T细胞淋巴瘤。最近，我们发现，N-末端截短的RXR？(tRXR?)导致蛋白水解裂解的RXR？在癌细胞中与细胞质中的PI 3 K相互作用以介导TNF？信号和非甾体抗炎药（NSAID）舒林酸可以结合tRXR？来调节tRXR TNF？信号通路（Cancer Cell 17，560，2010）。有趣的是，以前的一项研究表明，tRXR？在从13名胰腺导管腺癌患者建立的所有细胞系中高度产生。然而，tRXR的作用？在胰腺癌细胞的生长和耐药性是未知的。因此，我们假设tRXR？在胰腺癌的发展和胰腺癌细胞对化疗的抵抗中起着关键作用，tRXR？是治疗胰腺癌的潜在靶点。在这个试点研究的建议，我们将通过执行以下具体目标来解决这些假设：（1）研究tRXR的作用？在促进胰腺癌细胞的生长和耐药性;（2）确定tRXR？用于药物靶向的表面结合位点。我们的应用程序，其中建议确定tRXR的作用？在促进胰腺癌细胞生长和耐药性方面的研究，并验证新的药物靶点，具有探索性和新颖性。该项目预计将产生新的信息，为未来广泛的tRXR致癌潜力的机制研究奠定基础？以及通过R 01资助机制发现胰腺癌治疗药物。

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.