title: mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas.
abstract: OBJECTIVE
  The incidence of head and neck squamous cell carcinomas (HNSCC) associated with human papillomavirus (HPV) infection has increased over the past decades in the United States. We aimed at examining the global impact of HPV-associated HNSCC and whether the established key role of mTOR activation in HNSCC is also observed in HPV(+) HNSCC lesions, thereby providing novel treatment options for HPV-associated HNSCC patients.
  
  
  METHODS
  An international HNSCC tissue microarray (TMA) was used to analyze the expression of p16(INK4A), a surrogate for HPV infection, and Akt-mTOR pathway activation. Results were confirmed in a large collection of HPV(-) and HPV(+) HNSCC cases and in a cervical cancer (CCSCC) TMA. Observations were validated in HNSCC and CCSCC-derived cell lines, which were xenografted into immunodeficient mice for tumorigenesis assays.
  
  
  RESULTS
  Approximately 20% of all HNSCC lesions could be classified as HPV(+), irrespective of their country of origin. mTOR pathway activation was observed in most HPV(+) HNSCC and CCSCC lesions and cell lines. The preclinical efficacy of mTOR inhibition by rapamycin and RAD001 was explored in HPV(+) HNSCC and CCSCC tumor xenografts. Both mTOR inhibitors effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden. These results emphasize the emerging global impact of HPV-related HNSCCs and indicate that the activation of the mTOR pathway is a widespread event in both HPV(-) and HPV-associated HNSCC and CCSCC lesions.
  
  
  CONCLUSIONS
  The emerging results may provide a rationale for the clinical evaluation of mTOR inhibitors as a molecular targeted approach for the treatment of HPV-associated malignancies.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Christina
authors.initials: C
authors.lastname: Marsh
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Dinali
authors.forename: Nitin
authors.initials: N
authors.lastname: Gangane
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Jennison
authors.forename: Stephen
authors.initials: S
authors.lastname: Hewitt
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D009363:Neoplasm Proteins; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046888:Tissue Array Analysis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D009363:Neoplasm Proteins; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus