title: Novel actions of next-generation taxanes benefit advanced stages of prostate cancer.
abstract: OBJECTIVE
  To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.
  
  
  METHODS
  Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response.
  
  
  RESULTS
  The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel.
  
  
  CONCLUSIONS
  Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Renée
authors.initials: R
authors.lastname: de Leeuw
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Berman-Booty
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ciment
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: William K
authors.initials: WK
authors.lastname: Kelly
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Trabulsi
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Costas D
authors.initials: CD
authors.lastname: Lallas
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania. karen.knudsen@jefferson.edu.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D043823:Taxoids / Q000494:pharmacology*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel