Prediction of treatment response and ultrastructural analysis of resistance mechanisms in head and neck carcinomas in the xeno-free ex vivo model

• Applicant: Dr. Elena Seiz
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549152081

The survival rate of patients with head and neck cancer (HNSCC) is minimized by the development of resistance. Despite multimodal therapy concepts, the survival rate of HNSCC patients has not been improved in recent decades. The planned funding project over 12 months will investigate the role of mitochondria in the development of resistance in HNSCC. Mitochondria are the power plants of the cell that produce the energy messenger ATP. They regulate metabolism in tumor cells and contribute to the development of a tumor-friendly environment. Processes such as bypassing cell death and the immune system play a major role. Tumors can avoid the effects of chemotherapy by transporting the active ingredient away from the cancer cell. This happens through transmembrane proteins. The ex vivo model, in which small tumor samples from patients and healthy tissue are experimentally treated, is suitable for studying the production of transmembrane proteins and the change in the structure of mitochondria. The advantage is the 3D image of a tumor, which is more similar to the situation in humans. The samples are treated for 10 days with the common chemotherapy drug for HNSCC, Cisplatin. Cisplatin is said to promote the production of MDR1 (Multidrug Resistance-Related protein), a transport protein that is significantly involved in the transport of chemotherapy drugs and thus in the development of resistance. Mitochondrial metabolism can be influenced by inhibitors of transcription (mitochondrial RNA polymerase inhibitors) and translation (the antibiotic Doxycycline). The inhibition causes fewer mitochondrial proteins to be formed, which are necessary for ATP production. This is intended to inhibit the activity and formation of MDR1. The result would be an accumulation of cisplatin in the cancer cell. This could make the drug work better and avoid a resistance mechanism. However, mitochondria are also found in healthy cells. In order to minimize side effects and toxicity on healthy cells, further studies as part of the follow-up application will determine factors that distinguish mitochondria of cancer cells from healthy cells in order to be able to provide specific and targeted therapies. This therefore represents an opportunity in the future to improve the response to tumor therapies and to increase the life expectancy of cancer patients.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Annette Affolter