Mechanisms of the DNA double-strand break repair deficiency and radiation sensitivity in HPV-positive head and neck cancer cells

• Applicant: Dr. Thorsten Rieckmann
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Otolaryngology, Phoniatrics and Audiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514616755

In many western countries the incidence of squamous cell carcinoma of the head and neck (HNSCC) caused by high-risk types of the human papilomavirus (HPV) has been increasing continuously in the past years. These HPV-induced tumors have been shown to posess an enhanced sensitivity towards radiotherapy. Due to the resulting high cure rates and the often particularly high therapy-related side effects in HNSCC patients and the serious long-term limitations in quality of life, various clinical studies are currently underway to de-escalate the at present highly intensive therapies. Regarding the causes of the increased tumor radiation sensitivity, we and others have described an already high radiation sensitivity on the cellular level due to a severely restricted ability to repair radiation-induced DNA double-strand breaks. At present, various publications regarding the molecular nature of this DNA repair defect exist, but the statements are often contradictory and difficult to reconcile with one another. Since decisive experiments were often performed in a very limited number of HPV-positive HNSCC cell lines or in non-HNSCC tumor cells and since we could not confirm various of the suggested findings, we believe that there is still a fundamental need for clarification of the specific molecular mechanisms. The aim of this project is therefore to decode these molecular mechanisms of impaired DNA repair in HPV-positive HNSCC cells.For this purpose, the double-strand break repair pathways used by HPV-positive and HPV-negative HNSCC cells will be investigated and compared in competitive reporter gene assays at the molecular resolution. Furthermore, the kinetics of the radiation response of HPV-positive and HPV-negative HNSCC cells on the level of signal transduction (kinome), the level of mRNA expression (transcriptome) and the level of chromatin-associated protein interactions (chromatin-associated proteome) will be compared in detail. In addition to these open experimental approaches, HPV-modulated repair-associated factors that have not yet been adequately investigated, some of which have been identified in our own preliminary work, are to be examined for their specific influence on DNA repair in HPV-positive HNSCC cells. Thorough testing of identified factors and mechanisms in various other HPV-positive HNSCC cells and models will be performed to check their general validity for HPV-positive HNSCC. Unravelling these molecular processes shall identify targets for really HPV-specific therapies and in the medium-term enable profound protection of the normal tissues and prevention of therapy-related toxicities.

• DFG Programme: Research Grants