Pancreatic cancer is an abhorrent malignancy with limited diagnostics and response to drug therapy. It is believed that noncoding RNAs (ncRNAs) will further the understanding behind the mechanisms of pancreatic cancer development and progression, providing a novel approach for drug development and biomarker discovery. Therefore, a database of pancreatic cancer ncRNAs was established using bioinformatics and text mining approaches. These ncRNAs were characterized for RNA expression, copy number variation, disease association, single nucleotide polymorphisms, secretome analysis, and identification of protein targets. Exosomal proteins and ncRNA identified through this study provide the basis for noninvasive diagnostic potential. Additionally, a secreted microRNA, MIR3620, emerged from this study as a potential prognostic and diagnostic biomarker for pancreatic cancer. By analyzing MIR3620 and its protein targets, a mechanism of regulation for these genes in contributing to the progression and development of pancreatic cancer was established. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Indiana University-Purdue University Indianapolis (IUPUI) / Fatty acid synthase (FASN) is over-expressed in many cancers, and novel inhibitors that target FASN may find use in the treatment of cancers. It has been shown that orlistat, an FDA approved drug for weight loss, inhibits the thioesterase (TE) of FASN, but can be hydrolyzed by TE. To understand the mechanisms of TE action and for designing better FASN inhibitors, I examined the mechanism of orlistat hydrolysis by TE using molecular dynamics simulations. I found that the hexyl tail of orlistat undergoes a conformational transition, destabilizing a hydrogen bond that forms between orlistat and the active site histidine. A water molecule can then hydrogen bond with histidine and become activated to hydrolyze orlistat. These findings suggest that rational design of inhibitors that block hexyl tail transition may lead to a more potent TE inhibitor. To search for novel inhibitors of TE, I performed virtual DOCK screening of FDA approved drugs followed by a fluorogenic assay using recombinant TE protein and found that proton pump inhibitors (PPIs) can competitively inhibit TE. PPIs, which are used for the treatment of gastroesophageal reflux and peptic ulcers, work to decrease gastric acid production by binding irreversibly with gastric hydrogen potassium ATPase in the stomach. Recently, PPIs have been reported to reduce drug resistance in cancer cells when used in combination with chemotherapeutics, although the mechanism of resistance reduction is unknown. Further investigation showed that PPIs are able to decrease FASN activity and cancer cell proliferation in a dose-dependent manner. These findings provide new evidence that FDA approved PPIs may synergistically suppress cancer cells by inhibiting TE of FASN and suggests that the use of PPIs in combinational therapies for the treatment of many types of cancer, including pancreatic cancer, warrants further investigation.