Determining the function of the tumour suppressor serine-threonine kinase LKB1 in cancer

In Canada, the projected number of new cases of cancer for 2003 is estimated to be 139900, of which colorectal cancer represents 13%. Approximately 5% of these colorectal cancers will be inherited. Within the spectrum of colorectal cancers is a family of inherited syndromes that is responsible for the development of gastrointestinal polyps and associated cancer. A recent addition to this family is Peutz-Jeghers syndrome (PJS). PJS patients are at a greater risk of developing cancers of epithelial tissue origin, such as gastrointestinal, breast, ovaries, colon, pancreas, testicles and lungs. The gene responsible for PJS was recently discovered to be a tumour suppressor protein kinase called LKB1. It is believed that the loss of LKB1 kinase activity leads to PJS. However, the signalling mechanisms that lead to PJS are not fully understood. The development of cancer therapies and ultimately cures relies on a thorough understanding of how otherwise normal signalling pathways become aberrant. I propose a multidisciplinary approach that employs techniques such as reverse genetics and mass spectrometry in association with traditional biochemistry and molecular biology to better understand the molecular basis for PJS. My research program will identify key signalling partners of LKB1, thus providing critical information about the disease mechanisms mediated by loss of LKB1 tumour suppressor function. These findings will make clear the normal signalling pathway mediated by this kinase and confirm whether PJS and the associated malignancies are attributed to loss of kinase activity or loss of association with interacting partners. The research from my laboratory will potentially lead to the development of anti-cancer agents or strategies for gene therapy that will specifically target the LKB1 substrate and/or downstream molecules interacting with the LKB1 signalling pathway.