Kulkarni, A.; (2009) Aberrant regulation of the DNA replication licensing system and Aurora kinases in epithelial ovarian carcinoma. Doctoral thesis , UCL (University College London).

Abstract

Despite advances, the impact on long-term survival for individuals with epithelial ovarian carcinorna (EOC) remains modest. To date, efforts to find novel treatment strategies have focused on complex upstream oncogenic signalling pathways. However exploiting the molecules which govern these redundant pathways in the clinical setting has proved difficult. An alternative approach is to focus on the cell cycle machinery, which acts as an integration point for information transduced through upstream pathways. The DNA replication licensing factors and Aurora kinases are important cell cycle regulatory proteins which are showing promise as novel biomarkers and therapeutic targets in a broad range of tumour types. However there is a paucity of information regarding the role of these G1/S and G2/M regulatory molecules in EOC. Here I show that there is aberrant regulation of the DNA replication licensing system and Aurora kinases in EOC. Moreover, dysregulation of these molecules is associated with aggressive, genomically unstable tumour phenotypes, which in turn translates into important prognostic information with regards to patient survival. Furthermore, I have shown that multi-parameter expression analysis of these proteins allows assessment of cell cycle kinetics in individual pathological specimens, parameters linked to the biological behaviour of these tumours. This form of analysis could be utilised as a predictive test for therapeutic agents targeting the cell cycle machinery or upstream growth signal transduction pathways that accelerate cell cycle progression. Notably, my work identifies the Cdc7 and Aurora A kinases as promising predictive biomarkers and molecular targets in this complex tumour type, an intriguing finding in view of the nature of these molecules and their amenability to small molecule inhibition. Thus, finally, I have utilised in vitro RNA interference studies to provide early proof-of-principle validation that Cdc7 kinase represents a novel mechanism-based therapeutic target in this heterogeneous malignancy. Collectively, these studies highlight the prognostic, predictive and therapeutic utility of the DNA replication licensing system and Aurora kinases in EOC.

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