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Clin Cancer Res. 2017 Dec 1;23(23):7276-7287. doi: 10.1158/1078-0432.CCR-17-1438. Epub 2017 Sep 15.

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

Author information

1
Department of Surgery, Division of Otolaryngology, Yale University, New Haven, Connecticut.
2
Department of Medicine, Division of Medical Oncology, Yale University, New Haven, Connecticut.
3
Yale Cancer Center, Yale University, New Haven, Connecticut.
4
Department of Surgery, Division of Otolaryngology, Yale University, New Haven, Connecticut. natalia.issaeva@yale.edu wendell.yarbrough@yale.edu.
5
Department of Pathology, Yale University, New Haven, Connecticut.

Abstract

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.

PMID:
28916527
DOI:
10.1158/1078-0432.CCR-17-1438
[Indexed for MEDLINE]
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