A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model

Rheal A. Towner, Michael Ihnat, Debra Saunders, Anja Bastian, Nataliya Smith, Roheeth Kumar Pavana, Aleem Gangjee

High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule. GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively. Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors. Tumor volumes (21-31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls. Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors. It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells. These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.