Novel Iron-Targeted Therapy Is Highly Effective in Treatment-Resistant High-Grade Glioma in Vivo
Al-Gizawiy M, Wujek R, Prah M, Knipstein J, Alhajala H, Doan N, Molino S, Mirza S, Chitambar C, and Schmainda K. Novel Iron-Targeted Therapy Is Highly Effective in Treatment-Resistant High-Grade Glioma in Vivo. J Neurooncol 2019; 21:AA116.
BACKGROUND: Chemo-and radioresistance are characteristic features of post-treatment high-grade glioma (HGG). The cell populations responsible for this treatment-resistant phenotype are glioma stem cells (GSCs). These GSCs have a high requirement for iron which is essential for tumor cell viability. Intriguingly, the transferrin receptors that play a crucial role in iron uptake by both adult and pediatric astrocytomas exhibit a high affnity for gallium maltolate (GaM), a novel iron mimetic. Given the added commonality between adult and pediatric glioma stem cell signatures, especially post-treatment, we believe targeting treatment-resistant cell populations via their inherent iron metabolism is a viable approach to combat treatment-resistant HGG in adults and children. Here, we demonstrate the profound effects of GaM in a novel in vivo model of recurrent glioblastoma. METHODS: Irradiated human GBM cells (adult or pediatric) were stereotactically implanted into the right striatum of male athymic rats. Following confrmation of in vivo tumor growth by MRI at 9.4T, animals received GaM (50 mg/kg/day) in an oral preparation for voluntary ingestion. Tumor growth was monitored weekly by MRI, and lesion volume and associated advanced MRI parameter maps were determined using enhancing tumor ROIs. RESULTS: In a first set of animals, the mean weekly tumor growth rates of enhancing lesions were 65.8% and 156% in GaM-treated and control rats, respectively (p=0.002). Median disease-specifc survival was 51 days in GaM-treated animals and 28 days in controls (p=0.004). Complete response was observed in 20% of the animals, with complete resolution of the disease confrmed histo-logically. A partial response was observed in 40% of the animals. Follow-up data is being collected in a second set of animals for verification and updated results will be discussed. CONCLUSION: We present compelling evidence that iron-targeted therapy using the novel iron mimetic GaM is highly effective in treatment-resistant HGG.