224. Irradiation of glioma initiating cells-driven orthotopic glioblastoma after delivering of ATM inhibitor KU60019 as a radiosensitizer

Abstract

Purpose To investigate the radiosensitizing capacity and therapeutic efficacy of the ataxia-telangiectasia mutated (ATM) inhibitor KU60019 on orthotopic glioblastoma (GB) driven by primary glioma initiating cells (GIC) with various p53 statuses. Methods Orthotopic GB have been developed in mice by intracranial injection of different GIC lines. Following tumor development, KU60019 was delivered to the site of the tumor [1] . The irradiation of orthotopic GB was performed by an RS 2000 Biological Irradiator (Rad Source Technologies) whose delivered dose was verified by a RadCal Accu-Gold system (Monrovia) equipped with a 10X6-0.6 High Dose Rate Chamber. The dose was confirmed by radiochromic films (Gafchromic® EBT3) placed over and under the mouse head. The prescription dose ranged 0.5–2.5 Gy. MRI of the orthotopic tumors was performed by a clinical 3T scanner (Signa EXCITE®HDxT, GE, Milwaukee, USA) with mice positioned in a prototype coil (linear birdcage transmit/receive coil, Flick Engineering Solutions BV-General Electric). Tumor volumes were determined by a software for quantitative MRI (GRES) [2] . Results A limited, but significant, elongation of median animal survival was observed after one radiosensitization cycle performed with one KU60019 CED administration followed by three ionizing radiation (IR) fractions as compared to animals treated with vehicle + IR [101 vs 91 days – Hazard Ratio: 4.922]. Other irradiation schedules failed to improve survival of animals bearing orthotopic GBs. Conclusions Further research to determine general and effective conditions for radiosensitization of orthotopic GBs by ATM inhibitors is warranted.