Abstracts Category : Other

Exploiting mitosis to improve anti-cancerstrategies

by Ailsa Bennett

Antimitotics are used in cancer chemotherapy forthe treatment of cancers such as breast, ovarian, lung andprostate. Despite the success of agents such as Taxol, problemshave emerged such as side effects, resistance and the lack ofability to predict patient responsiveness. As a result, a class ofsecond-generation inhibitors have been developed with the aim toovercome or improve these issues. Such inhibitors target proteinsand kinases involved in the control of mitosis and the cell cycle.However, these have yet to be clinically successful and therefore,this highlights the requirement for an increased understanding ofthe mitotic process and how antimitotics truly elicit their action.Reasons for the lack of efficacy may be due to the absence ofbiomarkers to stratify patients into those likely to respond totreatment. It may also be possible that other targets are required.Our understanding of the action of antimitotics is thereforeparamount to improving cancer chemotherapy. By exploiting mitosisand understanding what happens when mitosis goes wrong, this thesisaims to explore new and improved methods of targeting, but alsoproposes to improve our understanding of the consequences ofaberrant mitoses through the use of small molecule inhibitors. Inthe first case the thesis investigated the targeting of the spindlecheckpoint protein Bub1 with 2OH-BNPP1, where previously inhibitorsagainst the kinase were not acknowledged. However the inhibitorused was not effective in cells and therefore furtherexperimentation was not possible. Secondly, to explore theconsequences of mitotic perturbation, an assay to exploreaneuploidy was established. To do this a Cenp-E inhibitor GSK923295was synthesised, which was subsequently used in assays with theMps1 inhibitor AZ3146 to generate aneuploidy progeny. The Cenp-Einhibitor was then used as an antimitotic agent in the finalchapter to explore the mechanism of action of mitotic blockers anddrivers often used in cell biology and clinical settings. Evidencesuggests that the intrinsic apoptotic pathway is activated uponexposure to these agents. With focus on this pathway, theimportance of Bcl-xL on cell survival was considered, revealingparticular importance in the post-mitotic response. Ultimately,this thesis should contribute to devising new and improvedanti-cancer strategies.Advisors/Committee Members: JACKSON, DEAN DA, Jackson, Dean, Taylor, Stephen.