Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose:DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation and survival. Here, we determined activity of a global DNA demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in pre-clinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMPs) in HPV+ HNSCC, activated interferon response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy.

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