title: Taxane mechanisms of action: potential implications for treatment sequencing in metastatic castration-resistant prostate cancer.
abstract: BACKGROUND
  In the past few years, there has been a rapid increase in the number of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC). Currently, approved treatments consist of the taxane class of cytotoxic drugs and androgen-targeted therapies. The challenge for clinicians is to decide the best sequence in which to give these therapies to provide the greatest benefit to their patients.
  
  
  OBJECTIVE
  To review recent research into the mechanism of action of taxanes in prostate cancer (PCa) cells and the clinical evidence for an interaction between taxanes and androgen-targeted therapies. The implications of these findings for clinical practice are discussed.
  
  
  METHODS
  A nonsystematic review of the relevant medical literature between 2004 and the present, in combination with clinical trial data reported at oncology meetings during 2012, was undertaken. Our perspective, focussing on the potential implications for sequencing of therapies for mCRPC, is provided.
  
  
  RESULTS
  Taxanes are shown to interact with androgen signalling in PCa cells at both the cytoplasmic level (via microtubules) and the nuclear level, affecting transcriptional regulators of androgen-responsive gene expression. Data from clinical trials suggest that androgen deprivation can potentially decrease the efficacy of taxanes in treating PCa.
  
  
  CONCLUSIONS
  These findings have important implications for clinical practice, and there is an urgent need for strong clinical data to support a recommendation for an optimal sequence of therapies.
authors.affiliation: Irish Cancer Society and University College Dublin School of Medicine and Medical Science, Dublin, Ireland. Electronic address: jfitzpatrick@irishcancer.ie.
authors.forename: John M
authors.initials: JM
authors.lastname: Fitzpatrick
authors.affiliation: Erasmus University Medical Center and Rotterdam Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
mesh_terms: D000728:Androgens / Q000378:metabolism; D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001549:Benzamides; D004347:Drug Interactions; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone
keywords: Abiraterone; Cabazitaxel; Castration-resistant prostate cancer; Docetaxel; Enzalutamide; Therapy sequence