[18F]FSPG-PET provides an early marker of radiotherapy response in head and neck squamous cell cancer

The ability to image early treatment response to radiotherapy in head and neck squamous cell carcinoma (HNSCC) will enable the identification of radioresistant tumor volumes suitable for treatment intensification. Here, we propose the system x_c ^- radiotracer (4<i>S</i>)-4-(3-[¹⁸F]fluoropropyl)-L-glutamate ([¹⁸F]FSPG) as a non-invasive method to monitor radiation response in HNSCC. We assessed temporal changes in cell death, antioxidant status, and [¹⁸F]FSPG retention following a single dose of 10 Gy irradiation in FaDU HNSCC cells. Next, using a fractionated course of radiotherapy, we assessed tumor volume changes and performed [¹⁸F]FSPG-PET imaging in FaDU-bearing mouse xenografts, followed by ex vivo response assessment. In cells, 10 Gy irradiation reduced [¹⁸F]FSPG retention, coinciding with the induction of apoptosis and the production of reactive oxygen species. In vivo, [¹⁸F]FSPG tumor retention was halved seven days after the start of treatment, which preceded radiotherapy-induced tumor shrinkage, thereby confirming [¹⁸F]FSPG-PET as an early and sensitive marker of radiation response.