Abstract

The molecular major characteristics of pancreatic cancer have now been relatively well characterised. This enables the preclinical and clinical testing of the combination of molecular targeted agents in conjunction with radiotherapy. Pancreatic cancer is characterised by a high rate of mutations in K-Ras (>90%) and p53 (50-75%). Inhibition of Ras as well as of upstream (EGFR) and downstream pathways of Ras were tested clinically to enhance cytotoxicity of radiotherapy to pancreatic cancer cells. As ATM -signalling is suppressed in the context of K-Ras and p53 mutations, targeting of ATR /Chk1 as the activated backup pathway for DNA double strand breaks appears to be an attractive strategy to be combined with radiotherapy. Furthermore, pancreatic cancer is a prime example of a tumour with a rich stromal reaction (desmoplasia) and pancreatic stellate cells which drive this reaction have been recognised to contribute to radiation resistance of pancreatic cancer. The stromal reaction also contributes to the dramatic hypoxia found in pancreatic cancers, one of the most important factors of radiation resistance, and signal transduction inhibitors of the EGFR /Ras/PI3 kinase/Akt pathway have been recognised to lead to a prolonged reoxygenation. These examples of using molecular strategies in conjunction with radiotherapy are given to reflect possible future strategies to improve outcomes.