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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested <i>in vivo</i> 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.<b>Results:</b> 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.<b>Conclusions:</b> 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. <i>Clin Cancer Res; 23(23); 7276-87. ©2017 AACR</i>.