title: Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation.
abstract: Resistance to docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel-pretreated and docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model.
  
  
  
  Intratumoral concentrations of docetaxel and cabazitaxel were correlated with antitumor activity in docetaxel-naïve, docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer.
  
  
  
  Intratumoral drug levels were negatively related to intrinsic and acquired resistance to docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs.
  
  
  
  The superior antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to docetaxel resulting from suboptimal intratumoral docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927-936, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: de Morrée
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: van Soest
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Aghai
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Corrina
authors.initials: C
authors.lastname: de Ridder
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Inge
authors.initials: I
authors.lastname: Ghobadi Moghaddam-Helmantel
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Mathijssen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Wiemer
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wytske
authors.initials: W
authors.lastname: van Weerden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000032:analysis / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000737:chemistry / Q000178:diet therapy* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000187:drug effects; D043823:Taxoids / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide
keywords: docetaxel-resistant prostate cancer; enzalutamide-resistant prostate cancer; intratumoral concentrations; patient-derived xenografts; taxanes