Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-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 preclinical 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, and 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 (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.

Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276–87. ©2017 AACR.

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