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 treatment is that current inhibitors have limited central nervous system (CNS) bioavailability.
The aim of their paper “Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice.” Karlin J, Allen J, Ahmad SF, Hughes G, Sheridan V, Odedra R, et. al. 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 growth and brain function. 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 a radiosensitizer in syngeneic and human, orthotopic mouse glioma models compared with AZ31. Furthermore, human glioma cell lines expressing mutant p53 or having checkpoint-defective mutations were particularly sensitive to ATMi radiosensitization. Image guided radiation therapy was delivered using the Small Animal Radiation Research Platform (SARRP).
The mechanism for this p53 effect involves a propensity to undergo mitotic catastrophe relative to cells with wild-type p53. In vivo, apoptosis was greater than 6-fold higher in tumor relative to healthy brain after exposure to AZ32 and low-dose radiation.
They found that 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.
This Xstrahl In Action was adapted from a article found on a National Library of Medicine website.