Epothilones and new analogues of the microtubule modulators in taxane-resistant disease

Abstract

Background: Microtubule-stabilising agents typified by the epothilone class of drug have demonstrated promising activity in Phase II and III clinical trials. Objective: Data supporting the efficacy of these agents are reviewed and their potential use in taxane-refractory disease assessed. Methods: Preclinical evidence assessing the role of the spindle assembly checkpoint in determining the cellular response to microtubule stabilization are presented together with clinical data documenting the efficacy of non-taxane microtubule modulators. Results/conclusions: Evidence suggests that microtubule-stabilising agents prolong activation of the spindle assembly checkpoint which may promote cancer cell death in mitosis or following mitotic exit. A weakened spindle assembly checkpoint is associated with altered sensitivity to agents targeting the microtubule and therefore pathways of drug resistance may be shared by these cytotoxic therapies. Preliminary clinical trial data do suggest modest activity of epothilones in truly taxane-resistant patient cohorts, indicating the potential niche for these agents in a molecularly undefined patient group, potentially implicating the role of P-glycoprotein in the acquisition of taxane-resistant disease. Trial data of these antimitotic agents will be presented together with their potential role in taxane-resistant disease and the implications for future clinical trial design.