TY - JOUR
T1 - The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models
AU - Durant, Stephen T.
AU - Zheng, Li
AU - Wang, Yingchun
AU - Chen, Kan
AU - Zhang, Lingli
AU - Zhang, Tianwei
AU - Yang, Zhenfan
AU - Riches, Lucy
AU - Trinidad, Antonio G.
AU - Fok, Jacqueline H.L.
AU - Hunt, Tom
AU - Pike, Kurt G.
AU - Wilson, Joanne
AU - Smith, Aaron
AU - Colclough, Nicola
AU - Reddy, Venkatesh Pilla
AU - Sykes, Andrew
AU - Janefeldt, Annika
AU - Johnström, Peter
AU - Varnäs, Katarina
AU - Takano, Akihiro
AU - Ling, Stephanie
AU - Orme, Jonathan
AU - Stott, Jonathan
AU - Roberts, Caroline
AU - Barrett, Ian
AU - Jones, Gemma
AU - Roudier, Martine
AU - Pierce, Andrew
AU - Allen, Jasmine
AU - Kahn, Jenna
AU - Sule, Amrita
AU - Karlin, Jeremy
AU - Cronin, Anna
AU - Chapman, Melissa
AU - Valerie, Kristoffer
AU - Illingworth, Ruth
AU - Pass, Martin
N1 - Publisher Copyright:
Copyright © 2018 The Authors.
PY - 2018/6/20
Y1 - 2018/6/20
N2 - Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/ targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.
AB - Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/ targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase–related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.
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UR - http://www.scopus.com/inward/citedby.url?scp=85049155898&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aat1719
DO - 10.1126/sciadv.aat1719
M3 - Article
C2 - 29938225
AN - SCOPUS:85049155898
SN - 2375-2548
VL - 4
JO - Science Advances
JF - Science Advances
IS - 6
M1 - eaat1719
ER -