LAUSR

Simple Summary Head and neck cancer is the sixth most common malignancy worldwide and it affects approximately 50,000 patients annually in the United States. Current treatments are suboptimal and induce significant long-term toxicities that permanently affect quality of life. Novel therapeutic approaches are thus urgently needed to increase the survival and quality of life of these patients. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. The objective of this review is to provide a brief overview of the function of important epigenetic modifiers in head and neck cancer, and to discuss the results of past and ongoing clinical trials evaluating epigenetic interventions targeting these epigenetic modifiers in head and neck cancer patients. The field of epigenetic therapy in head and neck cancer is still nascent; however, it holds significant promise. Although more specific epigenetic drugs are being developed, we envision the rational design of clinical trials that will target a select group of head and neck cancer patients with epigenetic vulnerabilities that can be targeted in combination with immunotherapy, chemotherapy and/or radiotherapy, rendering higher and durable responses while minimizing chronic complications for patients with head and neck cancer. Abstract The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions.