Is System xc- a Suitable Target for Tumour Detection and Response Assessment with Imaging?

Abstract

System x_c^- is upregulated in cancer cells and can be imaged using novel radiotracers, most commonly with (4S)-4-(3-[¹⁸F]fluoropropyl)-L-glutamic acid (¹⁸F-FSPG). The aim of this review was to summarise the use of ¹⁸F-FSPG in humans, explore the benefits and limitations of ¹⁸F-FSPG, and assess the potential for further use of ¹⁸F-FSPG in cancer patients. To date, ten papers have described the use of ¹⁸F-FSPG in human cancers. These studies involved small numbers of patients (range 1-26) and assessed the use of ¹⁸F-FSPG as a general oncological diagnostic agent across different cancer types. These clinical trials were contrasting in their findings, limiting the scope of ¹⁸F-FSPG PET/CT as a purely diagnostic agent, primarily due to heterogeneity of ¹⁸F-FSPG retention both between cancer types and patients. Despite these limitations, a potential further application for ¹⁸F-FSPG is in the assessment of early treatment response and prediction of treatment resistance. Animal models of cancer have shown that changes in ¹⁸F-FSPG retention following effective therapy precede glycolytic changes, as indicated by ¹⁸F-FDG, and changes in tumour volume, as measured by CT. If these results could be replicated in human clinical trials, imaging with ¹⁸F-FSPG PET/CT would offer an exciting route towards addressing the currently unmet clinical needs of treatment resistance prediction and early imaging assessment of therapy response.

Keywords: redox status; response assessment; system xc−; treatment resistance; treatment response.

Figure 1

System x_c⁻ schematic. System x_c⁻ imports cystine in exchange for intracellular glutamate, providing a surrogate marker of GSH biosynthesis. ¹⁸F-FSPG is an L-glutamate derivative used as a PET biomarker to assess intracellular redox status in vivo through targeting of the system x_c⁻ transporter.

Figure 2

Normal biodistribution of ¹⁸F-FSPG. The ¹⁸F-FSPG imaging at 90 min p.i. (SUV range: 0–10) in a patient with a primary nasopharyngeal tumour. Coronal MIP imaging (A) shows normal physiological uptake of ¹⁸F-FSPG in the soft palate, liver, and pancreas with renal excretion, as well as pathological uptake in the primary tumour. Low background activity in the majority of organs was noted. Axial CT (B) and axial fused images (C) demonstrate the ¹⁸F-FSPG uptake in the primary tumour (SUV_max = 10.9). The Figure was created from data acquired by Park S. Y. et al. [14] and provided by Life Molecular Imaging (Berlin, Germany).

Figure 3

¹⁸F-FSPG vs. ¹⁸F-FDG imaging. ¹⁸F-FSPG scans (SUV range: 0–10) in a patient with metastatic NSCLC at intervals up to 90 min p.i. (A), demonstrating rapid accumulation in the primary and mediastinal metastatic deposits, comparable to a standard 60 min p.i. ¹⁸F-FDG PET scan (B). The Figure was created from data acquired by Baek S. et al. [37] and provided by Life Molecular Imaging.

Figure 4

Comparative imaging shows differential uptake of ¹⁸F-FSPG vs. ¹⁸F-FDG in some metastatic deposits. ¹⁸F-FDG coronal MIP imaging (A) vs. ¹⁸F-FSPG coronal MIP imaging (B) highlights two lesions, one in the right and one in the left lower pulmonary lobes, which are easily detectable with ¹⁸F-FSPG but poorly discernible with ¹⁸F-FDG. Both images are 60 min p.i., with SUV range: 0–10. The Figure was created from data acquired by Baek S. et al. [37] and provided by Life Molecular Imaging.