Pancreatic cancer is the fourth leading cause of cancer-related deaths in western countries and also one of the most devastating, with nearly identical incidence and mortality rates. By the time of diagnosis, the median survival is less than six months and only 5% of patients will survive after five years. Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of all pancreatic cancer; it is usually detected late in life, although precursor lesions called Pancreatic Intraepithelial Neoplasias (PanINs) are prevalent in young individuals. Early detection of lesions, when the tumor is still confined to the pancreas, allows for surgical resection combined with chemotherapy, which is currently the only treatment that shows substantial increase in life expectancy Unfortunately, early lesions are mostly asymptomatic and by the time of diagnosis PDAC has usually infiltrated surrounding tissues or has already metastasized. Thus, a better understanding of the initiation of PDAC, pancreatic tumor biology and the signaling pathways affected throughout PDAC progression will provide us with better tools to identify early stage biomarkers and to develop novel and more specific targets with therapeutic potential. In this study we propose to identify long non-coding RNAs (lncRNAs) that may be involved in the progression of pancreatic cancer. LncRNAs are a diverse group of transcripts that resemble mRNAs but do not encode proteins. Although it is not clear what fraction of the currently annotated lncRNAs are truly functional there is considerable evidence that lncRNAs are involved in cancer. Furthermore, several lncRNAs have been shown to function in regulatory pathways that are known to be altered in PDAC. LincRNAs have also been shown to be more tissue-specific than coding genes, which make them optimal for drug targeting, as well as good biomarker candidates. Previously, a microarray analysis identified lncRNAs that are differentially regulated in PDAC. However, the study queried only 76 well-annotated lncRNAs, whereas it is predicted that approximately 10,000 lncRNAs exist in the mammalian genome. In this study, we propose to perform a systematic approach to identify and characterize lncRNAs that could be important for the progression and/or maintenance of pancreatic cancer. The aims of this grant are to: 1. Identify lncRNAs in different stages of pancreatic adenocarcinoma tumors and circulating fluids using high throughput sequencing data and computational biology; 2. Select and validate a subset of lncRNAs differentially expressed in PDAC and healthy pancreas; and 3. Identify the functions and molecular pathways regulated by candidate lncRNAs. This is an exciting discovery based approach to characterize novel factors involved in PDAC biology.

R21CA188059

2014-09-01

2016-08-31