title: Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer.
abstract: OBJECTIVE
  To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014.
  
  
  METHODS
  The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated.
  
  
  RESULTS
  The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014-induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial-mesenchymal transition; and reduced cancer stem-like cells in the tumor.
  
  
  CONCLUSIONS
  These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC.
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan. Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan. Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Keller
authors.affiliation: Department of Urology, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. etkeller@umich.edu xsjurologist@163.com.
authors.forename: Shujie
authors.initials: S
authors.lastname: Xia
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan. Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan. etkeller@umich.edu xsjurologist@163.com.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D016328:NF-kappa B; D043823:Taxoids; D013764:Tetrahydronaphthalenes; D000077143:Docetaxel; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat