Grant: Project Grant

Triple negative breast cancer (TNBC) accounts for ~15% of early breast cancers, and 75% of TNBCs have poor prognoses. Our objective is to lower mortality and morbidity from these and other genomically unstable cancers, by developing therapeutic approaches that exploit tumour specific biology of genomic instability and DNA repair deficiency. We've developed single cell genome sequencing methods that for the first time allow measurement of mutations in single cells. This is important because catching mutations in the act allows us to see repair and damage processes active in tumours. We recently discovered using this method that breast and ovarian cancers with specific patterns of chromosome fracture that invert fragments of DNA are associated with relative insensitivity to platinum, a common treatment for TNBC and ovarian cancers.. In parallel work, we've observed DNA damage induced by small molecule stabilizers of DNA folding structures known as G-quadruplexes (G4). These form from stacking of G DNA bases and these structures block DNA replication and genes switching on/off. We found that cancers that can't repair DNA breaks are especially sensitive and we've recently tested this hypothesis in a phase 1 trial of potent G4-binding molecule CX5461, and have observed clinical activity. However, we lack an understanding of how engagement of G4 folding sites in the genome is modified in repair deficient contexts, insight needed to develop more potent G4 binding drugs. Using G4 targeting molecules and G4 detection methods, single cell sequencing, and DNA repair-deficient patient tumours, we will identify how common sites of G4 engagement result in patterns of CNA-SV mutation, identify how DNA repair deficiency changes G4 engagement, and define the role of G4-targeting in regulation of genomic expression. These insights will advance development of G4 targeting therapeutics for genomically unstable cancers by identifying factors associated with drug/molecule efficacy.