Future targets in pancreatic cancer

Because attempts at improving survival in pancreatic cancer with cytotoxic and biologic therapy have been modest at the most thus far, newer strategies of targeting the core signaling pathways implicated in pancreatic cancer are needed.

Previously, genetic mutations affecting genes such as TP53, KRAS, CDKN2A and SMAD4 were known to be associated, but a more recent genome-wide analysis has identified a broader range of aberrant pathways implicated in pancreatic cancer growth.[46] In most of the 24 cancers examined in this series, the majority of the genetic mutations were felt to be disrupting one or more of 12 core signaling pathways.

In pancreatic cancer, aberrations can occur in signal transduction and other pathways that promote cell survival and allow proliferation. These include KRAS,[47] PI3K/ Akt/mTOR,[49-50] EGFR,[52] insulin-like growth factor (IGF-1) (which is co-expressed with Src),[52] hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF).[53] There are embryonic developmental signaling pathways that also lead to progression such as the Hedgehog, Notch, and Wnt pathways. [54-57] Matrix metalloproteinases (MMPs) also play a part in promoting neovascularisation and tumour invasion, and abnormalities in core pathways involved in DNA repair as well as apoptosis control such as p53, SMAD/TGF-P and p14 AFR/p16 are also seen.[58-s9]

Finally there is also documented activity or upregulation of other factors such as cyclo-oxygenase,[60] focal adhesion kinase (FAK) (which in turn interacts with the IGF-1 receptor),[61] telomerase,[62] as well as cholecystokinin, gastrin and gastrin receptors.[63]

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