Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer

Abraham Moses; Rim Malek; Mustafa Tansel Kendirli; Pierre Cheung; Madeleine Landry; Marco Herrera-Barrera; Abbas Khojasteh; Monica Granucci; Syed A Bukhari; Jody E Hooper; Melanie Hayden-Gephart; Scott J Dixon; Lawrence D Recht; Corinne Beinat

doi:10.7150/thno.101882

Monitoring of cancer ferroptosis with [¹⁸F]hGTS13, a system xc- specific radiotracer

Theranostics. 2025 Jan 1;15(3):836-849. doi: 10.7150/thno.101882. eCollection 2025.

Affiliations

¹ Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁴ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁶ Department of Biology, Stanford University, Stanford, CA, 94305, USA.

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, characterized by resistance to conventional therapies and poor survival. Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has recently emerged as a promising therapeutic target for GBM treatment. However, there are currently no non-invasive imaging techniques to monitor the engagement of pro-ferroptotic compounds with their respective targets, or to monitor the efficacy of ferroptosis-based therapies. System xc-, an important player in cellular redox homeostasis, plays a critical role in ferroptosis by mediating the exchange of cystine for glutamate, thus regulating the availability of cysteine, a crucial precursor for glutathione synthesis, and influencing the cellular antioxidant defense system. We have recently reported the development and validation of [¹⁸F]hGTS13, a radiopharmaceutical specific for system xc-. Methods: In the current work, we characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [¹⁸F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing investigational compounds. We then associated changes in [¹⁸F]hGTS13 uptake with cellular glutathione content. Furthermore, we evaluated [¹⁸F]hGTS13 uptake in a rat model of glioma, both before and after treatment with imidazole ketone erastin (IKE), a pro-ferroptotic inhibitor of system xc- activity. Results: Treatment with erastin2, a system xc- inhibitor, significantly decreased [¹⁸F]hGTS13 uptake and cellular glutathione content in vitro. Dynamic PET/CT imaging of C6 glioma-bearing rats with [¹⁸F]hGTS13 revealed high and sustained uptake within the intracranial glioma and this uptake was decreased upon pre-treatment with IKE. Conclusion: In summary, [¹⁸F]hGTS13 represents a promising tool to distinguish cell types that demonstrate sensitivity or resistance to ferroptosis-inducing therapies that target system xc-, and monitor the engagement of these drugs.

Keywords: PET imaging; [18F]hGTS13; ferroptosis; system xc-.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Amino Acid Transport System y+ / metabolism
Animals
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / drug therapy
Brain Neoplasms* / metabolism
Brain Neoplasms* / pathology
Cell Line, Tumor
Ferroptosis* / drug effects
Fluorine Radioisotopes*
Glioblastoma* / diagnostic imaging
Glioblastoma* / drug therapy
Glioblastoma* / metabolism
Glioblastoma* / pathology
Humans
Male
Radiopharmaceuticals*
Rats
Rats, Sprague-Dawley

Substances

Radiopharmaceuticals
Fluorine Radioisotopes
Amino Acid Transport System y+