Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors

Talele, Surabhi; Zhang, Wenjuan; Chen, Jiajia; Gupta, Shiv K.; Burgenske, Danielle M.; Sarkaria, Jann N.; Elmquist, William F.

doi:10.1124/jpet.122.001230

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…A spatial distribution study of peposertib, a substrate of P-gp and Bcrp with P-gp being the dominant limiting factor, showed homogeneous distribution among six brain regions, with which our experiment shared the criteria for brain-region differentiation and dissection (Talele, Zhang, Oh, et al, 2022). Also, the brain regional distribution of P-gp substrates AZD1390, an ataxia telangiectasia mutated kinase (ATM) inhibitor, and alisertib, an aurora A kinase inhibitor, showed no statistically significant differences among brain regions (Talele, Zhang, Chen, et al, 2022). These results suggest that P-gp and/or Bcrp mediated efflux should be homogeneous among different brain regions.…”

Section: Discussionmentioning

confidence: 55%

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

Zhang,

Oh,

Zhang

et al. 2023

J Pharmacol Exp Ther

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Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-HDAC inhibitor that is being tested in pre-clinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread, and diffuse midline glioma (DMG), which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of pglycoprotein (P-gp) and breast cancer resistant protein (Bcrp), that are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp and the free partition coefficient K p,uu of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice.In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients.Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. Significance StatementThese results show that the CNS penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor in spinal cord. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both pre-clinical and clinical trial study design and may eventually help guide treatment for these devastating brain tumors in children.

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Section: Discussionmentioning

confidence: 55%

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

Zhang,

Oh,

Zhang

et al. 2023

J Pharmacol Exp Ther

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“…3A). These data were then applied to our previous pharmacokinetic analysis of total AZD1390 measured in the tumor core and rim of orthotopic GBM12 xenografts and adjacent normal brain at 4 and 12 hours after a single oral dose (20 mg/kg) ( 22 ). Multiplying these published data by the unbound fraction provided an estimation of the free drug concentration of 265 ± 115 and 25 ± 12 nM in the tumor core and 56 ± 5 and 6.9 ± 4.0 nM in the tumor rim at 4 and 12 hours, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, the radiosensitizing effects on actively dividing stem and progenitor cells in hippocampi warrant careful risk assessment. AZD1390 is a brain-penetrant ATM inhibitor, and concentrations in normal brain can reach the threshold required to sensitize actively dividing GBM cells ( 22 ). Especially with even higher concentrations of AZD1390 achievable in the human brain, evaluating the impact of AZD1390 combined with brain irradiation on cognitive ability will be relevant.…”

Section: Discussionmentioning

confidence: 99%

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

Chen,

Laverty,

Talele

et al. 2024

Sci. Transl. Med.

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ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.

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How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors

Zhang,

Oh,

Zhang

et al. 2023

Pharm Res

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Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors

Cited by 6 publications

References 47 publications

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors

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