Dr Robert Jones - PhD
We are analyzing the feasibility of enhancing the efficacy of conventional cancer therapies by targeting the checkpoint kinase Chk1. Chk1 is a serine/threonine checkpoint kinase which is activated by the DNA damage caused by ionizing radiation and many chemotherapeutic agents. Activated Chk1 causes cell cycle arrest, which allows for DNA repair to occur and helps the cancer cell survive. Using cell culture we and others have been able to show that inhibition or loss of Chk1 can significantly enhance cytotoxic activity of cancer drugs, thus indicating that inhibitors of Chk1 may be useful in cancer therapy.
However it is not yet clear how Chk1 inhibition will affect normal somatic cells and tissues. In order to do this we have specifically targeted the Chk1 gene in mouse intestinal epithelial cells, using the AhCre LoxP system, in combination with a Chk1flox allele. Loss of Chk1 causes rapid induction of DNA damage followed by a wave of apoptosis in these cells. They are then replaced by re-populating stem cells containing functional Chk1, showing that loss of Chk1 is lethal to the cell but the integrity of the organ remains intact. This indicates that in therapy both the dose and duration of any Chk1 inhibitor therapy will crucial for its toxicity profile. We are currently using the same Cre LoxP system to look at the role of Chk1 in the liver.
High levels of apoptosis are seen when Chk1 is deleted in mouse intestinal epithelial cells as demonstrated by activation of caspase 3.
We are also interested in investigating the role of Chk1 in carcinogenesis. There is limited data suggesting that Chk1 may act as a dose dependent tumour suppressor. We are therefore currently investigating whether Chk1 status influences tumour formation and progression in the murine intestine. In order to do this we have introduced the Chk1 flox allele into an APCmin background. APCmin mice normally develop adenomas and therefore we are investigating if loss of one or both Chk1 alleles can influence the natural history of this process.