Abstract 5476: Simultaneous targeting of multiple cancer-related pathways in HPV-positive head and neck cancer with demethylating agents

Abstract

Abstract Head and neck cancer is the 6th most common cancer worldwide with the vast majority being squamous cell carcinoma (SCC). The human papillomavirus (HPV) has recently been shown to be the etiologic agent in approximately 60% of head and neck SCC (HNSCC) arising from the oropharynx. Patients with HPV-positive HNSCC are clinically distinct from those with HPV-negative cancer being younger, and having decreased exposure to the established risk factors for HNSCC of tobacco and alcohol. Although HPV-positive HNSCC patients have higher cure rates compared to HPV-negative HNSCC, lifelong side effects of treatment are severe, and upon recurrence, treatment options and survival are limited. Therefore, new therapies with better side effect profiles that can also offer therapeutic options for patients with recurrent HPV-associated HNSCC are needed. Recently, we found that HPV-positive head and neck cancer cell lines and primary cells were more sensitive than HPV-negative cells to the demethylating agent 5-azacytidine. Importantly, even low doses of 5-azacytidine delayed HPV-positive tumor growth in mouse xenograft model. Cancer-related pathways that we found to be altered in HPV-positive, but not in HPV-negative head and neck cancer cells, upon demethylation included: 1) restoration of tumor suppressor p53 levels and associated apoptotic activity; 2) activation of cytotoxic type I interferon response; and, 3) downregulation of matrix metalloproteinase (MMP1 and MMP10 ) expression. Demethylation as a therapy for HPV-associated HNSCC is particularly interesting, since simultaneous targeting of multiple molecular pathways that are important for cancer development and progression, may increase efficacy and reduce acquisition of resistance. Based on our data, a small clinical trial with 5-azacytide on patients with HNSC C was initiated at Yale Cancer Center. Citation Format: Asel Biktasova, Evgenia Gubanova, Mi Zou, Wendell G. Yarbrough, Natalia Issaeva. Simultaneous targeting of multiple cancer-related pathways in HPV-positive head and neck cancer with demethylating agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5476. doi:10.1158/1538-7445.AM2014-5476