We focus on mechanisms generating cancer genetic diversity and its consequences on clinical outcome. Our group and others, through next generation sequencing studies, have demonstrated that the principles of Darwinian and punctuated evolution apply to the growth and adaptation of human tumours.
Our group has demonstrated that intratumour heterogeneity, through tumour sampling bias, impacts upon our ability to successfully qualify cancer biomarkers for clinical use. We have also found evidence for extensive parallel evolution in human tumours, with multiple spatially separated subclones acquiring distinct mutations in the same gene, protein complex or signal transduction pathway, suggesting profound constraints to tumour evolution that might be exploited for therapeutic benefit. We are developing approaches to target mutations present in every tumour cell (clonal or trunk mutations) by leveraging the patient’s immune system to target clonal neo-antigens.
Finally, we are building on recent findings from our group that DNA replication stress, genome doubling events, HLA loss of heterozygosity, cytotoxic therapies and the APOBEC mutational process appear to contribute to intratumour heterogeneity and accelerate cancer evolution, in order to develop deeper insight into how patterns of cancer diversity may be limited for patient benefit.
Through the integration of our work with the UCL Cancer Trials Centre and UCL Cancer Institute and the Royal Marsden and Guys Hospitals we are recruiting into the TRACERx studies in Lung and Renal Cancers to decipher evolutionary processes, and the DARWIN (Deciphering Anti tumour Response With INtratumour heterogeneity) trial program aimed at understanding the impact of cancer diversity upon therapeutic outcome and how cancers evolve and adapt to therapy.