Grant: Banting Postdoctoral Fellowship Program

High grade serous ovarian cancer (HGSC) is the hardest to treat ovarian cancer with around 2800 cases in Canada each year. Despite its severity, little is known about the mutations to each tumour's DNA that allows it to spread and ultimately lead to mortality. These tumours can be treated with chemotherapeutic drugs but over time they become resistant to treatment. Discovering the molecular features that allow tumours to evade chemotherapy and what is unique about the subset of patients in which this happens would allow us to design novel therapies to prevent this. The lack of progress in understanding these DNA mutations has been in part due to difficulty measuring them. However, in the last two years the technology has sufficiently advanced (pioneered by researchers at BCCA) to measure both DNA mutations and RNA expression (a proxy for each cell's behaviour) in individual tumour cells. Researchers in the Shah group will apply these techniques to HGSC tumours over time as the tumours are exposed to different chemotherapy drugs to uncover the mutations that accompany chemotherapy resistance. However, this wealth of data will be impossible to interpret without a new statistical framework. We will create methods that allow us to reconstruct the "tree of life" for each tumour sample - allowing us to work out which cells mutated from others and in doing so tracking the sequences of mutations that confer resistance to chemotherapy. We will extend this methodology to understand mutations over time as cells are perturbed by the applications of various drugs and to work out the relative contributions of the cells' innate resistance (mutations) and adaptive resistance (by changing their gene expression behaviour) to chemotherapy resistance. This research has strong potential to impact clinical care as it will lead to new understandings of why certain patients don't respond to chemotherapy and could culminate in new treatment methods to suppress chemotherapy resistance.