title: Chemoprevention of head and neck cancer by simultaneous blocking of epidermal growth factor receptor and cyclooxygenase-2 signaling pathways: preclinical and clinical studies.
abstract: OBJECTIVE
  We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I).
  
  
  METHODS
  We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib.
  
  
  RESULTS
  The combined treatment inhibited head and neck cancer cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell-cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK, and pS6 levels after treatment, which correlated with clinical response.
  
  
  CONCLUSIONS
  Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. Clin Cancer Res; 19(5); 1244-56. ©2013 AACR.
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine Atlanta, Georgia 30322, USA.
authors: Dong M
authors: DM
authors: Shin
authors: Hongzheng
authors: H
authors: Zhang
authors: Nabil F
authors: NF
authors: Saba
authors: Amy Y
authors: AY
authors: Chen
authors: Sreenivas
authors: S
authors: Nannapaneni
authors: A R M Ruhul
authors: AR
authors: Amin
authors: Susan
authors: S
authors: Müller
authors: Melinda
authors: M
authors: Lewis
authors: Gabriel
authors: G
authors: Sica
authors: Scott
authors: S
authors: Kono
authors: Johann C
authors: JC
authors: Brandes
authors: William J
authors: WJ
authors: Grist
authors: Rachel
authors: R
authors: Moreno-Williams
authors: Jonathan J
authors: JJ
authors: Beitler
authors: Sufi M
authors: SM
authors: Thomas
authors: Zhengjia
authors: Z
authors: Chen
authors: Hyung Ju C
authors: HJ
authors: Shin
authors: Jennifer R
authors: JR
authors: Grandis
authors: Fadlo R
authors: FR
authors: Khuri
authors: Zhuo Georgia
authors: ZG
authors: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D011720:Pyrazoles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068579:Celecoxib