Exploiting synthetic lethality in ovarian cancer

Abstract

The term ovarian cancer describes a set of distinct and heterogeneous diseases with an overall poor prognosis. Standard treatment strategies are limited and new novel therapies targeting the molecular pathways dysregulated in ovarian cancer are being explored with a goal of personalising provision of treatment, based upon accurate biomarker testing. There are two major challenges if progress is to continue with a measureable clinical impact. Firstly, the mechanism of action of emerging therapies must be understood with reliable biomarkers capable of accurately predicting response to therapy. Secondly, for biomarkers to be useful in their accurate prediction of response, a thorough understanding of how to test a patient is needed. As our understanding of inter- and intra-tumour heterogeneity grows, the ability to test a single sample of tumour that is representative becomes more challenging and it is likely that new clinical strategies for testing multiple areas of the same tumour, at multiple time points, are required if our understanding of tumour biology is to translate into survival benefit for patients. Detection and subsequent testing of circulating tumour cells may offer the ability to test cells representative of the entire tumour without the need for invasive testing but a clear understanding of the consequences of intra-tumoural heterogeneity is needed. This PhD aimed to address these challenges by firstly exploring the potential role of sapacitabine, a novel oral nucleoside analogue, for the treatment of ovarian cancer alongside the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib and platinum. Homologous recombination DNA repair functional status has been explored as a biomarker for their stratified use. Additionally, this project aimed to explore the feasibility of detecting circulating tumour cells in ovarian cancer using ImageStream technology, which combines flow cytometry with high resolution immunofluorescent microscopy.