An orthotopic xenograft model of metastatic nasopharyngeal carcinoma and its application in elucidating a therapeutic target that inhibits metastasis.

e13536 Background: Nasopharyngeal carcinoma (NPC) is a serious health problem in many parts of the world. Although rare in the United States and Western Europe, it is the leading form of cancer in men between the ages of 20-44 years in parts of southeast Asia, and is prevalent in Indonesia, North Africa, the Middle East, amongst Eskimo populations, and represents one of the most frequent epithelial tumors of children in geographically higher risk areas. Current treatment protocols have resulted in good clinical outcomes if the disease is diagnosed and treated at an early stage. Unfortunately, metastatic NPC is refractory to treatment and carries an extremely poor prognosis. Particularly concerning is, that among head and neck cancers of epithelial origin, it is associated with the highest rate of metastasis. This highlights the need for models that are amenable to the study of metastatic NPC and adequate to test new potential therapies. Methods: In order to define and therapeutically target mechanisms that mediate nasopharyngeal carcinoma (NPC) metastasis, we have developed a unique orthotopic xenograft mouse model that accurately recapitulates the invasive and metastatic behavior of human disease. Results: Based on published clinical data and gene array analysis we performed on biopsy samples, we concluded that the PI3K/Akt/mTOR axis is involved in aggressive NPC tumor behavior. We thus chose it as a therapeutic target to test the utility of our orthotopic system for evaluating the effectiveness of a targeted treatment for metastatic NPC. We have subsequently demonstrated that both the development and growth of metastatic lesions are markedly reduced by the mTOR inhibitor sirolimus. Conclusions: Thus, this orthotopic model provides a platform to study potential therapeutics for advanced NPC and demonstrates that targeting the PI3K/Akt/mTOR pathway is a promising intervention against disseminated disease.