title: Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.
abstract: BACKGROUND
  Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.
  
  
  METHODS
  We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.
  
  
  RESULTS
  Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.
  
  
  CONCLUSIONS
  IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
authors.affiliation: Department of Vincent Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: McCann
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.forename: Kashmira
authors.initials: K
authors.lastname: Kulkarni-Datar
authors.forename: Michael D
authors.initials: MD
authors.lastname: Curley
authors.forename: Anne M
authors.initials: AM
authors.lastname: Friel
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Proctor
authors.forename: Hana
authors.initials: H
authors.lastname: Sheikh
authors.forename: Igor
authors.initials: I
authors.lastname: Deyneko
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Ferguson
authors.forename: Vinod
authors.initials: V
authors.lastname: Vathipadiekal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.forename: Gayatry
authors.initials: G
authors.lastname: Mohapatra
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Zukerberg
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.forename: John R
authors.initials: JR
authors.lastname: Macdougall
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D060046:Maintenance Chemotherapy; D051379:Mice; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C541444:IPI-926; D012333:RNA, Messenger; C509239:SHH protein, human; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine