Moses Abraham, Malek Rim, Kendirli Mustafa Tansel, Cheung Pierre, Landry Madeleine, Herrera-Barrera Marco, Khojasteh Abbas, Granucci Monica, Bukhari Syed A, Hooper Jody E, Hayden-Gephart Melanie, Dixon Scott J, Recht Lawrence D, Beinat Corinne
Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Theranostics. 2025 Jan 1;15(3):836-849. doi: 10.7150/thno.101882. eCollection 2025.
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.
多形性胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的原发性脑肿瘤，其特点是对传统疗法具有抗性且生存率低。铁死亡是一种由脂质过氧化驱动的程序性细胞死亡形式，最近已成为GBM治疗中一个有前景的治疗靶点。然而，目前尚无无创成像技术来监测促铁死亡化合物与其各自靶点的结合情况，或监测基于铁死亡疗法的疗效。系统xc-是细胞氧化还原稳态中的一个重要参与者，通过介导胱氨酸与谷氨酸的交换在铁死亡中起关键作用，从而调节半胱氨酸的可用性，半胱氨酸是谷胱甘肽合成的关键前体，并影响细胞抗氧化防御系统。我们最近报道了[F]hGTS13的开发和验证，[F]hGTS13是一种针对系统xc-的放射性药物。在当前工作中，我们表征了各种细胞系对促铁死亡化合物的敏感性，并评估了[F]hGTS13区分敏感和耐药细胞系以及监测对诱导铁死亡的研究性化合物反应变化的能力。然后，我们将[F]hGTS13摄取的变化与细胞内谷胱甘肽含量相关联。此外，我们评估了在给予咪唑酮厄拉司丁（IKE，一种系统xc-活性促铁死亡抑制剂）治疗前后，[F]hGTS13在大鼠胶质瘤模型中的摄取情况。用系统xc-抑制剂厄拉司丁2治疗显著降低了[F]hGTS13摄取和细胞内谷胱甘肽含量。用[F]hGTS13对荷C6胶质瘤大鼠进行动态PET/CT成像显示，颅内胶质瘤内有高且持续的摄取，而在用IKE预处理后这种摄取减少。总之，[F]hGTS13是一种有前景的工具，可用于区分对靶向系统xc-的诱导铁死亡疗法表现出敏感或抗性的细胞类型，并监测这些药物的结合情况。
