Pancreas Cancer Research
Abstract:
Pancreatic carcinoma has a dismal prognosis and is largely resistant to current chemotherapeutic agents. Knowledge of the mechanisms involved in the development and progression of this disease is limited. Improved understanding of the cell-signalling pathways involved would allow identification of markers to predict disease progression and outcome and allow development of novel targeted therapies. The aim of this Ph.D. thesis is to elucidate the role of the Notch signalling pathway in pancreatic cancer and to investigate potential therapeutic avenues to modulate this pathway. The Notch pathway consists of four transmembrane receptors activated by a gamma-secretase enzyme upon ligand binding. Notch is known to regulate the differentiation of epithelial precursors during normal organogenesis, whilst in the adult pancreas it maintains a pool of stem cells. Aberrant activation of Notch favours tumour formation, and recent research suggests that the Notch pathway may play a part in the carcinogenesis of several solid and haematological malignancies.
Our work to date has demonstrated that the Notch pathway is upregulated in resected pancreatic carcinoma specimens compared to normal pancreatic ductal epithelium, and nuclear expression is suggestive of pathway activation. Such activation is associated with aggressive tumour phenotype and poor prognosis. In vitro, we have demonstrated that treatment with a gamma-secretase inhibitor (?SI) inactivates the Notch pathway. It also resulted in reducted cell proliferation and viability, associated with cell cycle arrest and the induction of apoptosis. Treatment with ?SI also enhances the sensitivity to current chemotherapeutic agents, including Gemcitabine. We are currently investigating the contribution of the individual Notch pathway constituents to these effects and have shown specific inhibition of Notch 1 using siRNA to result in reduction of cell proliferation and viability. These data suggests Notch to be important in pancreatic carcinogenesis and ?SIs to be promising novel chemotherapeutic agents, Our future work will concentrate on elucidating the mechanisms involved in these effects with the ultimate aim of trialling this class of drug in patients with pancreatic cancer.
