Constitutive Overexpression of the Oncogene Racl in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor
Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence.
We gratefully acknowledge Marc Symons for helpful suggestions and critical reading of the manuscript. This work was supported by grants 5R01DC00203, 5R01DC008579, 1R01DC008579-S1 and 1F32DC011446 from the National Institute on Deafness and Other Communication Disorders.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Deafness and Other Communication Disorders or the National Institutes of Health. Celecoxib and matching placebo were provided by grant 2004-0029 (WS287683) from Pfizer Global Pharmaceuticals, New York, New York, USA.
Celecoxib was used for the clinical study and was obtained through a grant from Pfizer.
- 3.Wu R, Abramson AL, Shikowitz MJ, Dannenberg AJ, Steinberg BM. (2005) Epidermal growth factor-induced cyclooxygenase-2 expression is mediated through phosphatidylinositol-3 kinase, not mitogen-activated protein/extracellular signal-regulated kinase kinase, in recurrent respiratory papillomas. Clin. Cancer Res. 11:6155–61.CrossRefGoogle Scholar
- 5.Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors: impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7:493–507.Google Scholar
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