2. Academic Validation
  3. Monitoring of cancer ferroptosis with [18F]hGTS13, a system xc- specific radiotracer

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.
Abraham Moses 1,  Rim Malek 1,  Mustafa Tansel Kendirli 2,  Pierre Cheung 1,  Madeleine Landry 1,  Marco Herrera-Barrera 3,  Abbas Khojasteh 2,  Monica Granucci 4,  Syed A Bukhari 5,  Jody E Hooper 5,  Melanie Hayden-Gephart 4,  Scott J Dixon 6,  Lawrence D Recht 2,  Corinne Beinat 1
Affiliations

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.
PMID: 39776801 DOI: 10.7150/thno.101882
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-.

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