Abstract 6506: Targeting ATM with AZD1390 for radio-sensitization of glioblastoma patient derived xenografts
Authors: Jiajia Chen, Shiv K. Gupta, Gaspar J. Kitange, Ann C. Mladek, Brett L. Carlson, Lihong He, Zeng Hu, Katrina K. Bakken, Danielle M. Burgenske, Margaret A. Connors, Jann N. Sarkaria
Journal: Cancer Research (2020)

Abstract The efficacy of standard radiation therapy (RT) in glioblastoma (GBM) is limited, and there is a strong rationale to develop effective radiosensitizing agents. ATM is a key regulator of DNA damage induced by RT, and small molecule ATM inhibitors have shown radio-sensitizing effects in cancer cells, and may improve radio-sensitivity in GBM. Here, we evaluated the brain penetrant ATM inhibitor AZD1390 in combination with RT in GBM cell lines and patient derived xenografts (PDXs). AZD1390 (30 nM and higher) suppressed ionizing radiation-(5 Gy, IR) induced phosphorylation of ATM-Serine1981 and downstream signaling proteins Kap1, Chk2 and H2AX in GBM established cell lines (U251 and U87) and PDX lines (GBM12, GBM39 and GBM43). In cell cycle analysis, 30nM AZD1390 enhanced the IR induced G2/M arrest in U251 (80.6% with AZD1390/IR vs. 64.6% with IR alone, p= 0.01) and PDX lines GBM43 (61.9% vs. 25.7%, p= 0.01) and GBM39 (40.9% vs. 25.4%, p= 0.01). Moreover, in a U251 clonogenic survival assay, AZD1390 sensitized cells to IR-(5 Gy) induced killing (0.24% survival with AZD1390/RT vs. 2.3% with IR alone, P=0.01). For in vivo radiation combination studies, mice with established orthotopic tumors were irradiated to the cerebrum through opposed laterals with a 225 kVp stereotactic animal irradiator. While the hard palate and upper tongue were in the radiation target, the oropharynx and hypopharynx were spared with this radiation set up. A pilot study of RT combined with AZD1390 was evaluated in mice with established U251 orthotopic tumors using cohorts of 5 mice per arm. AZD1390 was given concurrently with conventionally fractionated radiation (2 Gy x 5 fractions) at a dose of 20 mg/kg PO delivered either daily or twice daily, with or without the efflux inhibitor elacridar. RT alone was well tolerated with minimal weight loss but was ineffective (median survival 30 days vs. 33 days in control group, p=0.5). In contrast, all of the RT/AZD1390 treatment arms exhibited enhanced but tolerable weight loss and had significant extension in symptom-free survival that currently extends beyond 65 days (median survival no reached). In conclusion, AZD1390 is an effective radio-sensitizer in vitro, and survival benefit from AZD1390 combined with conventionally fractionated RT in U251 models is encouraging. Further evaluation of efficacy across additional PDX models and careful analysis of the pharmacodynamic effects in tumor vs. normal tissues will be important to understand the therapeutic window for this agent in combination with RT. Citation Format: Jiajia Chen, Shiv K. Gupta, Gaspar J. Kitange, Ann C. Mladek, Brett L. Carlson, Lihong He, Zeng Hu, Katrina K. Bakken, Danielle M. Burgenske, Margaret A. Connors, Jann N. Sarkaria. Targeting ATM with AZD1390 for radio-sensitization of glioblastoma patient derived xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6506.