TY - JOUR
T1 - Orally bioavailable and blood–brain barrier-penetrating ATM inhibitor (AZ32) radiosensitizes intracranial gliomas in mice
AU - Karlin, Jeremy
AU - Allen, Jasmine
AU - Ahmad, Syed F.
AU - Hughes, Gareth
AU - Sheridan, Victoria
AU - Odedra, Rajesh
AU - Farrington, Paul
AU - Cadogan, Elaine B.
AU - Riches, Lucy C.
AU - Garcia-Trinidad, Antonio
AU - Thomason, Andrew G.
AU - Patel, Bhavika
AU - Vincent, Jennifer
AU - Lau, Alan
AU - Pike, Kurt G.
AU - Hunt, Thomas A.
AU - Sule, Amrita
AU - Valerie, Nicholas C.K.
AU - Biddlestone-Thorpe, Laura
AU - Kahn, Jenna
AU - Beckta, Jason M.
AU - Mukhopadhyay, Nitai
AU - Barlaam, Bernard
AU - Degorce, Sebastien L.
AU - Kettle, Jason
AU - Colclough, Nicola
AU - Wilson, Joanne
AU - Smith, Aaron
AU - Barrett, Ian P.
AU - Zheng, Li
AU - Zhang, Tianwei
AU - Wang, Yingchun
AU - Chen, Kan
AU - Pass, Martin
AU - Durant, Stephen T.
AU - Valerie, Kristoffer
N1 - Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2018/8
Y1 - 2018/8
N2 - Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro. AZ32, with enhanced blood–brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses.
AB - Inhibition of ataxia-telangiectasia mutated (ATM) during radiotherapy of glioblastoma multiforme (GBM) may improve tumor control by short-circuiting the response to radiation-induced DNA damage. A major impediment for clinical implementation is that current inhibitors have limited central nervous system (CNS) bioavailability; thus, the goal was to identify ATM inhibitors (ATMi) with improved CNS penetration. Drug screens and refinement of lead compounds identified AZ31 and AZ32. The compounds were then tested in vivo for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells in vitro. AZ32, with enhanced blood–brain barrier (BBB) penetration, was highly efficient in vivo as radiosensitizer in syngeneic and human, orthotopic mouse glioma model compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was >6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation. AZ32 is the first ATMi with oral bioavailability shown to radiosensitize glioma and improve survival in orthotopic mouse models. These findings support the development of a clinical-grade, BBB-penetrating ATMi for the treatment of GBM. Importantly, because many GBMs have defective p53 signaling, the use of an ATMi concurrent with standard radiotherapy is expected to be cancer-specific, increase the therapeutic ratio, and maintain full therapeutic effect at lower radiation doses.
UR - http://www.scopus.com/inward/record.url?scp=85052383068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052383068&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0975
DO - 10.1158/1535-7163.MCT-17-0975
M3 - Article
C2 - 29769307
AN - SCOPUS:85052383068
SN - 1535-7163
VL - 17
SP - 1637
EP - 1647
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 8
ER -