title: Inhibition of gamma-secretase activity impedes uterine serous carcinoma growth in a human xenograft model.
abstract: OBJECTIVE
  Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity.
  
  
  METHODS
  Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods.
  
  
  RESULTS
  High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts.
  
  
  CONCLUSIONS
  Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Jolijn W
authors.initials: JW
authors.lastname: Groeneweg
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Tracilyn R
authors.initials: TR
authors.lastname: Hall
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Byron
authors.affiliation: Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Tambouret
authors.affiliation: Merck Oncology, Boston, MA, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathayanrayanan
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: wgrowdon@partners.org.
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D005260:Female; D018398:Homeodomain Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis*; D051881:Receptor, Notch1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology*; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D003499:Cyclic S-Oxides; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D013830:Thiadiazoles; D000072056:Transcription Factor HES-1; C523799:MRK 003; C497761:NOTCH1 protein, human; C078493:HES1 protein, human
keywords: Gamma secretase inhibitor; Notch; Patient derived xenograft model; Uterine serous carcinoma