Orally Bioavailable and Blood–Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice

Abstract

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 for efficacy and impact on tumor and healthy brain. Both AZ31 and AZ32 blocked the DNA damage response and radiosensitized GBM cells AZ32, with enhanced blood-brain barrier (BBB) penetration, was highly efficient 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., 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. .

Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells

“…It caused a relatively minor downregulation of (CBD + γ-irradiation)-induced apoptosis simultaneously with a strong upregulation of a ratio of the G2/M-arrested glioma cells that finally blocked glioma cell proliferation. Two recent publications also described the strong negative effects of new ATM kinase inhibitors combined with γ-irradiation on glioma cells and GBM development [54, 55].…”

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…ATM inhibition has been shown to be synthetic lethal in vitro in combination with APE1i or functional loss of XRCC1 [188,189]. ATM inhibitors (ATMi) are known potent radio-sensitizers, studied currently on in vitro and in vivo models mainly for its potential use in brain-tumors cancer therapy [218][219][220]. However, in vitro results show that ATMi sensitize different gynecological cancer cell lines (e.g., A2780 and OVCAR3 ovarian cancer cells, Table 2) to ionizing radiation as well [213].…”

DNA damage checkpoint kinases in cancer

“…The chemistry is different from that of the KuDos compounds and has been shown to be orally bioavailable as well as capable of crossing the blood-brain barrier in mice (Ref. 64). In vivo optimisation of AZ32 led to the development of AZD1390 sensitised brain tumours to radiotherapy in preclinical models justifying translation into a clinical trial (section ‘Clinical trials with ATM and CHK2 inhibitors’ ) (Ref.…”