title: Hedgehog inhibition enhances efficacy of radiation and cisplatin in orthotopic cervical cancer xenografts.
abstract: The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx).
  
  
  
  5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models. The xenografts were treated with radiotherapy (15 × 2 Gy daily fractions over 3 weeks) and weekly cisplatin 4 mg kg-1concurrently, with or without 5E1 or Sonidegib (LDE225). The Hh inhibitors were administered by subcutaneous injection (5E1; 20 mg kg-1weekly for 3 weeks), or by oral gavage (Sonidegib; 60 mg kg-1daily for 3 weeks).
  
  
  
  We observed that both Hh inhibitors administered with RTCT were well tolerated and showed increased tumour growth delay, and reduced metastasis, with no increase in acute GI-toxicity relative to RTCT alone.
  
  
  
  Our data suggest Hh can be a valid therapeutic target in cervical cancer and supports data suggesting a potential therapeutic role for targeting Hh in patients undergoing RTCT. This warrants further investigation in clinical trials.
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, Ontario MG5 2M9, Canada.
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.affiliation: Biostatistics Department, Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario MG5 2M9, Canada.|Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, Ontario MG5 2M9, Canada.|Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario MG5 2M9, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario MG5 2M9, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.affiliation: Ontario Cancer Institute/Princess Margaret Cancer Centre and The Campbell Family Institute for Cancer Research, Ontario MG5 2M9, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario MG5 2M9, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Ontario MG5 2M9, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Ontario MG5 2M9, Canada.|Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario MG5 2M9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario MG5 2M9, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Mackay
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage*; D004357:Drug Synergism; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011725:Pyridines / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; C465570:Shh protein, mouse; C561435:sonidegib; D002945:Cisplatin