Survival signaling and redox regulation in pancreatic ductal adenocarcinoma

Cancer-associated molecular abnormalities are known to affect the activity of cellular signaling networks. The potential to target activated survival signaling pathways and antioxidant-redox regulation to improve treatment response in pancreatic ductal adenocarcinoma is addressed in this thesis. An activated signaling profile distinguished cancer cells from morphologically normal duct cells in the adjacent normal pancreas as well as non-cancer pancreas surgical resections. A capacity of the PKB/Akt survival pathway to modulate gemcitabine sensitivity was examined using in vitro and in vivo experimental models. Inhibition of PI3K, the principle activator of PKB, or the suppression of total PKB enhanced gemcitabine cytotoxicity. However, a subset of cell lines displayed an inversion of gemcitabine sensitivity in vivo as compared to in vitro, suggesting that additional factors such as antioxidant-redox potential and tumor microenvironment influenced treatment response in vivo. An oxidative stress mediated apoptosis was examined as an alternative therapy using sulforaphane (SFN). The compound was tested on two cell lines that demonstrated resistance to gemcitabine as well as in combination with PI3K inhibition. A lower redox potential in PANC-1 cells was associated with a higher SFN-induced cytotoxicity and tumor growth inhibition. In this thesis, pancreatic cancer was sub-classified based on bio-functional characteristics including transcript and protein levels as well as chemotherapy response. These results give insight into the pathogenesis as well as potential treatment strategies for pancreatic cancer.