title: Generation of a patient-derived chordoma xenograft and characterization of the phosphoproteome in a recurrent chordoma.
abstract: OBJECTIVE
  The management of patients with locally recurrent or metastatic chordoma is a challenge. Preclinical disease models would greatly accelerate the development of novel therapeutic options for chordoma. The authors sought to establish and characterize a primary xenograft model for chordoma that faithfully recapitulates the molecular features of human chordoma.
  
  
  METHODS
  Chordoma tissue from a recurrent clival tumor was obtained at the time of surgery and implanted subcutaneously into NOD-SCID interleukin-2 receptor gamma (IL-2Rγ) null (NSG) mouse hosts. Successful xenografts were established and passaged in the NSG mice. The recurrent chordoma and the derived human chordoma xenograft were compared by histology, immunohistochemistry, and phospho-specific immunohistochemistry. Based on these results, mice harboring subcutaneous chordoma xenografts were treated with the mTOR inhibitor MLN0128, and tumors were subjected to phosphoproteome profiling using Luminex technology and immunohistochemistry.
  
  
  RESULTS
  SF8894 is a novel chordoma xenograft established from a recurrent clival chordoma that faithfully recapitulates the histopathological, immunohistological, and phosphoproteomic features of the human tumor. The PI3K/Akt/mTOR pathway was activated, as evidenced by diffuse immunopositivity for phospho-epitopes, in the recurrent chordoma and in the established xenograft. Treatment of mice harboring chordoma xenografts with MLN0128 resulted in decreased activity of the PI3K/Akt/mTOR signaling pathway as indicated by decreased phospho-mTOR levels (p = 0.019, n = 3 tumors per group).
  
  
  CONCLUSIONS
  The authors report the establishment of SF8894, a recurrent clival chordoma xenograft that mimics many of the features of the original tumor and that should be a useful preclinical model for recurrent chordoma.
authors.affiliation: Department of Neurological Surgery.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Davies
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Robinson
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cowdrey
authors.forename: Praveen V
authors.initials: PV
authors.lastname: Mummaneni
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ducker
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Andrew
authors.initials: A
authors.lastname: Bollen
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002817:Chordoma / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D000939:Epitopes; D064593:Heterografts / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010758:Phosphorus / Q000378:metabolism*; D020543:Proteome / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000939:Epitopes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D010758:Phosphorus; D020543:Proteome; D058570:TOR Serine-Threonine Kinases