RADT-02. Potent radiosensitizing effect of the novel metallocompound, gallium maltolate, for the treatment of glioblastoma in vivo

Introduction We seek to evaluate gallium maltolate (GaM) as a radiosensitizer for the treatment of brain malignancies. As an iron mimetic, gallium interferes with DNA repair by inhibition of ribonucleotide reductase, leading to cell death. These inhibitory effects on DNA repair mechanisms recommend GaM as a radiosensitizer. Methods Mitochondrial function and cellular bioenergetics were assessed in primary brain cancer cells treated with GaM and irradiated with 2Gy. Additionally, for this proof-of-concept pilot study, athymic rats were inoculated intracranially with glioblastoma (GBM) cells. After tumor confirmation on MRI, animals received oral GaM 50mg/kg/day or vehicle followed by radiation therapy [(RT); 21 Gy]. All preclinical MRI was performed on a 9.4T Bruker preclinical scanner. MRI studies were repeated every 10-14 days. Images were acquired as part of our custom preclinical acquisition protocol including pre- and post-contrast anatomical T1 and T2 sequences, and DSC perfusion imaging. Longitudinal MRS was collected from 2mm3 voxels placed in enhancing and non-enhancing areas. MRI data was processed using Imaging Biometrics and Bruker Paravision analysis software, as well as custom-made MATLAB scripts. Statistical analyses included linear mixed model analysis, Kaplan-Meier curves, as well as Student’s t-test or rank sum test. Results In addition to our in vitro findings, we present the data from one animal that has successfully surpassed the 6-month endpoint of our study. Pre-treatment with GaM+RT in vivo induces significant tumor shrinkage and survival benefit over GaM or RT monotherapy. Longitudinal MRS demonstrated development of necrosis and apoptosis, a return to normal tissue brain metabolism, and a loss in the choline to creatine ratio. Still, whereas these results are quite promising, we need to validate them in a larger cohort of animals. Conclusion The in vivo cytotoxic effect of GaM on GBM is potentiated by RT. This new discovery has the potential to change how brain cancer patients with limited therapeutic options are treated.