Exploiting the vulnerabilities of therapy-resistant cancer for improved efficacy of radiopharmaceutical therapy

• Applicant: Dr. Nils Trautwein
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580195928

Now radiopharmaceutical therapy (RPT) is one of the fastest-growing areas of medical treatment. However, despite therapeutic advances, the underlying molecular and cellular mechanisms governing treatment response and the emergence of resistance remain incompletely understood. Reactive oxygen species (ROS) and cellular senescence are known to have double edged roles in cancer therapy. In response to ROS cancer cells may rely on antioxidant enzymes and proteins, who act in a context-dependent manner to selectively counteract this type of cell death. The efficiency of radiotherapy can be enhanced due to concentration of molecular oxygen (O), as DNA damage induced by ROS generated during water (H₂O) radiolysis can react with O₂ to form superoxide anions. Since ROS levels are key mediators of radiation-induced cell death, resistance to radiation is often linked to reduced ROS production or the presence of a robust antioxidant defence system. Radiation therapy generates ROS within tumour cells, which represent a primary mechanism of radiation-induced DNA damage and subsequent cell death. Thus, ROS plays a pivotal role in determining the radio-resistance of tumour cells. To withstand radiation-induced oxidative stress, radio-resistant tumour cells often maintain elevated levels of reductants such as glutathione (GSH) or aldehyde dehydrogenases (ALDH). These antioxidants protect cells by neutralizing electrophiles and ROS, thereby limiting oxidative damage and supporting cell survival during radiation therapy. At King's College we would like to investigate whether the antioxidative system plays a key role in response to RPT. Furthermore, we aim to explore the role of ROS-induced senescence in this framework. As an experimental starting point, we will use two different lung cancer cell lines: NCI-H69 (SCLC) overexpresses SSTR2, while A549 (NSCLC) overexpresses ALDH1A1. We will first extensively characterise the antioxidative stress response of both cancer cell lines in vivo by [18F]F-NTx-10 targeting ALDH1A1 and [18F]FSPG PET to image the xc− system. Then we will treat these cell lines with RPT: NCI-H69 with Lutathera and A549 with [131I]I-NTx-11. Subsequently, we will characterize therapy-induced changes in the antioxidative system and will investigate therapy-induced senescence.

• DFG Programme: Fellowship
• International Connection: United Kingdom
• Host: Professor Tim Witney, Ph.D.