Investigation of circulating tumour DNA in the early detection of KRAS and EGFR mutant cancers. (360G-Wellcome-103799_Z_14_Z)

I plan to use my experience of genetically modified mouse cancer models together with clinical samples from cancer patients and screening cohorts obtained from a network of collaborators to investigate the potential of circulating free tumour DNA to enable the early detection and characterisation of cancers. Specific major research questions are: 1. Using mouse models, at what stage in the development of a tumour can circulating free tumour DNA be detected, and how does this compare with detec tion of the tumour using the most advanced pre-clinical imaging techniques? Focus will particularly be on models of tumours with high frequency of occurrence of mutant KRAS or EGFR (epidermal growth factor receptor) driver oncogenes, specifically KRAS mutant pancreatic cancer and KRAS or EGFR mutant non-small cell lung cancer. 2. What processes are involved in the release of circulating free tumour DNA and is it possible to find interventions that will promote its appearance in plasma or serum? If so, do these interventions impact on tumour progression? 3. Building on these results, is it possible to detect circulating free tumour DNA in patients with early stage pancreatic and lung cancer, comparing genotype with that of tumour biopsies? Analysing screening cohorts, is it possible to identify healthy individuals in high-risk groups who have evidence of circulating free tumour DNA in archived plasma or serum samples? Does this predict subsequent development of malignancy? These appr oaches will determine whether or not analysis of circulating free tumour is likely to have utility as a tool for early detection of cancers in the clinic and, if so, may provide insights into optimisation of its use.