Beyond taxanes: the next generation of microtubule-targeting agents

Abstract

Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician’s treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.

ATIP3, a Novel Prognostic Marker of Breast Cancer Patient Survival, Limits Cancer Cell Migration and Slows Metastatic Progression by Regulating Microtubule Dynamics

“…Microtubule-targeting drugs such as taxanes are used for standard first-line treatment of breast cancer metastasis, and new microtubule-targeting agents, such as epothilones and eribulin, are under clinical evaluation (10). Microtubules are polarized and highly dynamic structures that rapidly switch between periods of polymerization (growth) and depolymerization (shrinkage) at the plus ends, a process termed dynamic instability (11)(12)(13).…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…Both ixabepilone, a semi-synthetic epothilone derivative, and eribulin mesylate, an analogue of halichondrin B, have been FDA approved for patients with metastatic breast cancer whose disease has progressed despite prior anthracycline and taxane therapy (DybdalHargreaves et al 2015. Many other epothilone and halichondrin derivatives have shown promising antitumoral activity in preclincal studies; some of them are in clinical trials for the treatment of tumors of different histotypes and the results are eagerly awaited (Perez 2009, Cortes & Vidal 2012, Forli 2014). …”

Evaluation of [11c]mpc-6827 as a Microtubule Targeting Pet Radiotracer in Cancer Cell Lines

“…The application of these drugs has shown several limitations, however, such as neurological and bone marrow toxicity, and emergence of drug-resistant tumor cells due to the overproduction of multi-drug resistance-1 (MDR1), affinity to P-glycoprotein (p-GP) and breast cancer resistance protein (BCRP), and overexpression of different β-tubulins or tubulin mutations. To overcome these hurdles, several strategies are being developed to identify new MTAs as potential cancer therapeutics [27][28][29][30][31][32]. [33].…”