Abstract 841: Inhibition of head and neck squamous cell carcinoma growth by combination treatment of erlotinib and celecoxib: Potential chemopreventive agents

Abstract

Abstract The interaction of epithelial growth factor receptor (EGFR) and cyclooxygenase 2 (COX-2) pathways plays an important role in tumorigenesis. Our recent Phase I chemoprevention trial of premalignant lesions including pathologically moderate or severe dysplasia and carcinoma in situ in oral cavity and larynx showed a 71% (5/7) estimated overall response rate after a 6-month-long combination treatment of Erlotinib and Celecoxib without significant toxicities (ASCO 2010 Abstract # 5535). The current preclinical study was designed to investigate the underlying mechanisms that contribute to the inhibitory effect on the disease progression by the combined treatment of Erlotinib and Celecoxib. Chemopreventive efficacy was determined using a head neck squamous cell carcinoma (HNSCC) xenograft model with Tu212 cell line. Animals received vehicle control (0.1% Tween 80 and 0.5% methylcellulose, n=6), Celecoxib at 50mg/kg body weight (n=6), Erlotinib at 75mg/kg body weight (n=7), or combination of Erlotinib and Celecoxib (n=8) with the same dose as the single agent by oral gavaging daily for 6 days before subcutaneous implantation of cancer cells. Animals were further treated daily for 5 days per week with a total of 4 weeks. The combination treatment significantly suppressed tumor growth compared with Erlotinib alone (p=0.01), Celecoxib alone (p<0.0001) or the vehicle control (p<0.0001). In vitro study was performed with Tu212 and Tu686 HNSCC cell lines. Cell cycle analysis revealed that G1 arrest was induced by either Erlotinib alone (59% and 67% for Tu212 and Tu686, respectively), or Celecoxib alone (50% and 58% for Tu212 and Tu686 cells, respectively). The combination treatment resulted in greater G1 arrest than either single agent alone (72% in Tu212 and 65% in Tu686 cells). Molecular analysis showed that the combined treatment augmented suppression of pERK, pAKT and pEGFR. In addition, Erlotinib suppressed mTOR pathway by diminishing pS6. These results support the findings in the phase I study. The study has progressed to Phase II clinical trial. In conclusion, augmented inhibition of pEGFR/pERK/pS6 pathways could contribute to the synergism by Erlotinib and Celecoxib in suppressing HNSCC tumor growth. (This study is supported by NIH grant U01 CA151802 and P50CA128613 to Dr. Shin and Georgia Cancer Coalition Distinguished Cancer Scholar award to Drs Shin and Chen. *: These authors had equal contribution.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 841. doi:10.1158/1538-7445.AM2011-841