Diffusing Alpha-emitters Radiation Therapy (DaRT) in Combination with Bevacizumab in Human Glioblastoma Multiforme Xenografts

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy, and targeted therapy (e.g., the antiangiogenic agent Bevacizumab, BEV or Avastin). Diffusing Alpha-emitters Radiation Therapy (DaRT) is a new modality which employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with a standard-of-care therapy such as BEV was investigated. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in tumors large relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care antiangiogenic therapy is a promising approach, which may improve the treatment of GBM patients.