Novel combination strategies with Aurora Kinase Inhibitors: using pre-clinical data to guide clinical trial design

Anti-mitotic drugs such as paclitaxel are successful chemotherapeutics, but their utility is limited by toxicity and resistance. My research aimed to identify novel therapeutic strategies combining current drugs with aurora kinase inhibitors (AKI) in pre-clinical models and then to design a clinical trial to assess these in patients with bladder cancer. Particular interest was stimulated by the correlation between over-expression of aurora kinases (AKs) with aggressive clinical behaviour in many cancers and the network of interactions which AKs have with other key proteins. Pre-clinical studies suggested that the use of AKIs in combination with other drugs, particularly other anti-mitotic agents, might increase efficacy but this had not been studied in bladder cancer. As over-expression of AK-A can induce resistance to paclitaxel, I hypothesised that an AK-A inhibitor would synergistically enhance the cytotoxicity of paclitaxel. Human bladder cancer cell lines were used in cytotoxicity assays to study a range of novel AKIs as single agents and in combination with paclitaxel. Application of mathematical models identified regions of synergy when AK-A specific inhibitors were combined with low concentrations of paclitaxel in T24, RT112 and UM-UC-3 cell lines, with 80- 100% growth inhibition. The effects of these combinations on non-cancer cell lines and in neutrophil precursor cells demonstrated differential toxicity, with a reduced risk of myelotoxicity compared with higher dose paclitaxel, suggesting they may provide a better therapeutic window. Mechanistic investigations included live cell imaging, which showed a correlation between the time cells spent in mitosis and cell fate, and an assessment of the potential contribution of AK-A expression in sensitivity to the drug combination. Combinations of MLN8237 (an AK-A inhibitor) with paclitaxel and docetaxel were studied in a T24 bladder cancer xenograft model, and these confirmed tolerability with evidence of efficacy in tumour growth inhibition. Published clinical trials have now demonstrated the potential efficacy of AK-A inhibitors in combination with taxanes but at the expense of additive toxicity. My work suggests that using AK-A inhibitors with lower concentrations of paclitaxel could reduce toxicity, highlighting the need to explore a range of combinations. Existing early phase clinical data have emerged from trials using traditional rule-based trial designs, where limited dose ranges were explored. Therefore, an alternative novel Bayesian adaptive design should be considered to fully assess the efficacy of the combination of MLN8237 and paclitaxel.Cancer Research U