P16 in HPV related Head and Neck Carcinoma: Taken for surrogate marker, but being the radiobiological master switch?

Human papilloma virus (HPV) related head and neck cancer (HNSCC) is becoming a worldwide epidemic. The clinical behavior of these HNSCC’s differs very much from that of classical smoking and alcohol related HNSCC but the molecular basis for this is not understood: First, these tumors respond far better to radiotherapy than classical HNSCC. Further in contrast to classical HNSCC these tumors are unresponsive to hypoxia targeted therapy although they show similar levels of hypoxia. Interestingly, in HPV related disease, hypoxia seems to have no negative impact on radiotherapy effectiveness which is very surprising given the current radiobiological paradigms. In this project we hope to shed light on these questions by assessing the impact of p16 (which is strongly associated to HPV) on DNA repair through its function as a cyclin dependent kinase inhibitor, and, on tumor hypoxia tolerance through its negative regulatory impact on the HIF1α pathway. New insights from this project will help the clinical community to select the most relevant markers for response prediction and better insight into the molecular behavior of these cancers will lead to more intelligent clinical trial design testing new combinations of drugs in classical as well as HPV related HNSCC. Furthermore this study could also inspire the development of new therapeutic drugs targeting the HIF1α pathway.