Role of tRXRalpha in pancreatic cancer development and therapy

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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.