Project Summary/Abstract There is an emerging epidemic of head and neck cancer caused by human papillomavirus (HPV) among both smokers and nonsmokers. While vaccination of boys and girls prior to genital HPV exposure is likely to reduce HPV+ HNC, the impact of vaccination won’t be realized for decades. In the meantime, HPV+ HNC patients are treated with disfiguring surgeries and combined chemoradiation approaches, which are associated with significant short- and long-term morbidities. Individuals with recurrent/metastatic HPV+ HNC generally succumb to their disease. My research program will apply new approaches in functional genomics and mapping networks of physical interactions among cancer proteins in relevant and unique HPV+ HNC preclinical models to translate cancer dependencies in this malignancy into more effective and less toxic therapies. In this proposal, I build upon our past success in 1) defining key genomic “driver” alterations in HNC; 2) developing novel therapeutic approaches; and 3) translating our discoveries using relevant preclinical models into clinical treatments for HNC patients. My future research program seeks to 1) define the key genetic alterations that mediate HPV+ HNC growth in conjunction with determination of the protein interactome to identify new therapeutic targets; 2) determine the mechanisms of each target and its role in HPV+ HNC; and 3) translate these findings into new treatments for HPV+ HNC. I will begin with the study of targets that have emerged in our research as relevant in HPV+ HNC such as alterations that activate phosphatidylinositol 3- kinase (PI3K) signaling including mutation or amplification of PIK3CA, or PTEN loss, and activation of the EGFR family member HER3. When relevant, I will extend these findings to other HPV+ cancers including cervical and anal cancers as well as HPV- HNC, which remain lethal. With deep expertise in the molecular pathogenesis and care of patients with HNC; experience leading multi-disciplinary teams focused on translational research approaches for this disease and a rich network of basic science and clinical collaborators, I am uniquely positioned to succeed in the 7 year research plan delineated in this proposal.