Effect of oxidative stress response in HPV16 mediated oropharyngeal carcinogenesis

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Human papillomavirus (HPV) is a pivotal risk factor for the development of oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence reported in several countries. With a prevalence of more than 80%, high-risk HPV16 is the most common type detected in OPSCC. We recently showed that in both HPV16-positive and HPV-negative OPSCC, there is a subgroup characterized by oxidative/metabolic stress-related signatures and upregulation of aldo-keto-reductases, AKR1C1 and AKR1C3, going along with unfavourable prognosis. Upregulation of AKR1Cs prevents the accumulation of cytotoxic reactive oxygen species (ROS), an important mechanism leading to resistance against chemotherapeutic drugs such as cisplatin, which is used as a standard of care for OPSCC patients. The proposed grant application seeks to investigate the role of overexpressed AKR1Cs in HPV-induced OPSCC development. This study aims to understand the link between increased HPV16-E6*I expression, AKR1C1/C3 activation, and the associated metabolic reprogramming and oxidative stress in the context of malignant transformation. This grant covers the following two objectives: 1) To analyze the cell toxicity of a combination of AKR1C inhibitors and cisplatin on HPV-positive or -negative head and neck squamous cell carcinoma cell lines and on oral tumor development in HPV16 transgenic mice. 2) To determine the downstream effects of AKR1C1/C3 deregulation by HPV16 under oxidative stress on metabolic reprogramming. The aim of the study is to develop novel, de-escalating therapeutic approaches for HPV-induced tumours and thus define future treatment approaches for patients with favourable prognoses.