Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer.

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 preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV HNSCC. Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested 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. 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 (MMP) in HPV HNSCC, activated IFN response in some HPV head and neck cancer cells, and inhibited the ability of HPV xenografted tumors to invade mouse blood vessels. 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. .