Grant: Project Grant

Triple negative breast cancer (TNBC) accounts for ~15% of early breast cancers, and ~75% of TNBCs have poor prognosis. Similarly concerning, high grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy. Both cancers develop drug resistance; our objective is to lower mortality associated with these diseases by developing tools and methods that can identify therapeutic opportunities to overcome drug resistance. Cancers are dynamic systems changing in response to evolutionary pressure, and these processes occur differently in cells throughout a single tumour. Genome sequencing methods that evaluate patient tumours as a single blended genome, and do not distinguish individual cells, obscure these single cell processes. This proposal builds on work from my group and our collaborators over several years1-15. These enable study of cancer as a mosaic of distinct genomes, genomes that may individually lead to resistance to therapeutics like platinum, a common treatment for TNBC/HGSOC. Knowledge of these processes is currently limited to platinum treatment. The proposed project exploits principles of natural selection occurring during the course of disease to evaluate changes in cancer cell genomes, their activity, and DNA modifications altering that activity. The methods to be applied include sequencing of DNA and mRNA from individual cells, and sequencing of DNA base modifications affecting expression of mRNA from DNA. All of these methods will be applied in the context of tumour cell treatment with i) individual treatment with 400 different drugs and small molecules, ii) inhibitors of DNA modification, and iii) CRISPR, used to test if genes are essential to cell survival. These techniques, applied to patient tumours transplanted into lab mice or maintained as cultures of cells, will reveal potential therapeutic drug/molecule combinations, genetic markers associated with drug resistance, and genetic markers that can inform cancer treatment strategies.