Grant: Foundation Grant

Cancers evolve over time and the gene mutations driving them can change. A major bottleneck in the treatment of epithelial cancers is a lack of diverse therapeutic / treatment options. This is especially relevant in cancer, as tumours are able to evolve/adapt to "escape" from single-agent treatment (similar to what occurs in antibiotic-resistant bacteria, where a combination of drugs is required to treat the infection); breast cancers often develop drug resistance so that their tumors recur, and mutational evolution likely underlies this event. It is critical to identify new options/approaches to target tumours that have become drug-resistant, as a result of mutational evolution. We know that clonal complexity - the so called "cellular superbug" phenomenon, is associated with instability in the tumour's genetic sequence (driven by the inability of DNA to repair itself). We hypothesize that specific sections of the genome, with unique DNA structures may be targetable through directed approaches, and plan to explore novel approaches that target structural vulnerabilities within the human genome. By combining chemical genomics of DNA targeting with genetic technologies to uncover conditional genetic interactions and methods for measuring clonal structure, we expect to derive a completely new mechanistic approach to targeting genomically unstable epithelial cancers. Our studies have the potential to answer specific questions about how breast cancer arises, progresses, and becomes resistant to treatment. These findings will have a global impact within the cancer research community, allowing the design of improved and more effective therapies. In short, the practical application of cancer cell genetics will become a reality in the clinic -- representing a significant step forward in direct translational benefits for patients.