Integrating cell screening and mechanism of action data for organometallic anticancer agents
Jessica M. Hearn · Warwick Research Archive Portal (University of Warwick) · 2015
Both acquired and intrinsic drug resistance are established clinical problems in many areas of medicine. This is particularly evident with the growing resistance to platinum chemotherapy agents in cancer treatment programmes. New, alternative treatments for platinum-resistance patients are needed, with comparable potency, no platinum cross- resistance, better safety profiles and which target non-repairable areas of the cell, reducing acquired resistance. This thesis focuses on osmium- and iridium-based organometallic anticancer agents to fill this clinical need. Previous work has validated their potency, safety and activity in platinum-resistant cancers, however, their mechanism of action (MOA) was yet to be identified. Knowing the MOA of new compounds is essential for personalising and stratifying cancer treatment, allowing for better patient selection and prediction of treatment outcomes. Often identifying the biological target of a new therapeutic is not essential. Instead, quantifying the cellular response to that treatment, and identifying cell types which hold beneficial biological properties to optimise compound effects, is more effective. This thesis has applied the principles of systems biology to study the whole cell effect of osmium and iridium compounds in epithelial ovarian cancer. Cells were studied at the transcriptional, translational and structural level to investigate compound response, integrating a selection of these findings using novel statistical modelling. Results propose that these compounds induce oxidative stress in cancer cells, and subsequently damage DNA to exert antiproliferative effects at submicromolar concentrations. This is the first example of studying organometallic compounds using this combination of techniques, and is a promising work flow for future efforts in this area.