Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019

Abstract

We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K ("responder" genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the "responder" profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.

Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas

“…Disappearance of VE822 after NP-VE822 CED was well represented by a biexponential decay: ~45% of the drug was cleared with a half-life of 2 h, and the remainder of the drug was cleared more slowly with a half-life of 8.3 d. These data indicate that we can achieve sustained concentrations of VE822, a potent and selective DNA repair inhibitor, in the brain by CED of NP-VE822. In addition, these findings confirm previous literature findings demonstrating rapid clearance of small molecules from the brain parenchyma (20). …”

“…The use of CED in humans with intracranial tumors has been shown to be safe in both adults and children with gliomas (17–19). Although CED provides enhanced drug penetration, most small molecules administered directly to the brain are prone to rapid clearance from the brain parenchyma, which usually leads to undetectable drug levels 24 hours after the end of a course of CED (20). CED typically is only administered once because of the complexity and potential morbidity of the procedure.…”

Limited advances in therapy of glioblastoma trigger re-consideration of research policy

“…This is supported by the reduced therapeutic effect observed when orthotopic tumours are developed using primary GIC rather than established cell lines ( Fig. 1 and [14]). In other words, the profound polymorphic nature of humans and their tumours may damp the therapeutic effects in aggregate studies.…”

“…For instance, the observed short-lived clinical benefit of bevacizumab in GB [8,9] may not mean that bevacizumab cannot improve OS of GB patients but rather, that the employed treatment schedule was wrong. In our preclinical studies with ATM inhibitors as GB radiosensitizers, we observed efficacy under a narrow combination of ATM inhibitor concentration and radiation dose [14] and the treatment schedule was profoundly affected by the cell's environment: the same GIC line could be radiosensitized in our preclinical studies with different treatment schedules if grown into a petri dish or orthotopically in a mouse brain, and, most probably the same will happen when tumours will have to be treated in human brains (Fig. 2).…”

“…MRI of mouse GB reproduced from Ref. [14], with permission. MRI of human GB courtesy of Radiology Teacher file server http://www.radiologyteacher.com/ index.cgi?&nav=view&DatID=1125.…”