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

in Theranostics by 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

TLDR

  • The study developed a non-invasive imaging technique using [F]hGTS13 to monitor the engagement of pro-ferroptotic compounds with their targets and the efficacy of ferroptosis-based therapies for Glioblastoma multiforme (GBM).
  • The study found that [F]hGTS13 can distinguish between sensitive and resistant cell lines to ferroptosis-inducing therapies and monitor the efficacy of ferroptosis-based therapies in a rat model of glioma.

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 [F]hGTS13, a radiopharmaceutical specific for system xc-.In the current work, we characterized the sensitivity of various cell lines to pro-ferroptotic compounds and evaluated the ability of [F]hGTS13 to distinguish between sensitive and resistant cell lines and monitor changes in response to ferroptosis-inducing investigational compounds. We then associated changes in [F]hGTS13 uptake with cellular glutathione content. Furthermore, we evaluated [F]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.Treatment with erastin2, a system xc- inhibitor, significantly decreased [F]hGTS13 uptake and cellular glutathione content. Dynamic PET/CT imaging of C6 glioma-bearing rats with [F]hGTS13 revealed high and sustained uptake within the intracranial glioma and this uptake was decreased upon pre-treatment with IKE.In summary, [F]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.

Overview

  • The study focuses on developing a non-invasive imaging technique to monitor the engagement of pro-ferroptotic compounds with their targets and the efficacy of ferroptosis-based therapies for Glioblastoma multiforme (GBM).
  • The researchers used [F]hGTS13, a radiopharmaceutical specific for system xc-, to study the sensitivity of various cell lines to pro-ferroptotic compounds and its ability to monitor changes in response to ferroptosis-inducing investigational compounds.
  • The study aimed to associate changes in [F]hGTS13 uptake with cellular glutathione content and evaluate its uptake in a rat model of glioma before and after treatment with a pro-ferroptotic inhibitor.

Comparative Analysis & Findings

  • The study found that treatment with erastin2, a system xc- inhibitor, significantly decreased [F]hGTS13 uptake and cellular glutathione content, indicating that [F]hGTS13 can distinguish between sensitive and resistant cell lines to ferroptosis-inducing therapies.
  • Dynamic PET/CT imaging of C6 glioma-bearing rats with [F]hGTS13 revealed high and sustained uptake within the intracranial glioma, which was decreased upon pre-treatment with IKE, a pro-ferroptotic inhibitor of system xc- activity.
  • The study demonstrated that [F]hGTS13 can monitor the engagement of pro-ferroptotic compounds with their targets and the efficacy of ferroptosis-based therapies, providing a non-invasive imaging technique for GBM treatment.

Implications and Future Directions

  • The study suggests that [F]hGTS13 can be used as a promising tool for non-invasive imaging of GBM and monitoring the efficacy of ferroptosis-based therapies.
  • Future studies can investigate the translational potential of [F]hGTS13 in clinical trials and explore its combination with other therapies for enhanced anti-tumor effects.
  • Understanding the specificity and sensitivity of [F]hGTS13 in various tumor types and its optimization for effective imaging and therapy monitoring will be crucial for future applications.
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