ArticleThe Journal of pharmacology and experimental therapeutics2022
Central Nervous System Delivery of the Catalytic Subunit of DNA-Dependent Protein Kinase Inhibitor Peposertib as Radiosensitizer for Brain Metastases.
Article in The Journal of pharmacology and experimental therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 12 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic glioblastoma tumors.Neuro-oncology · 2025Article
- Unlocking the Therapeutic Potential of DNA-PKcs in Cancer: Comprehensive Insights into Mechanisms and Clinical Applications.Cancers · 2025Review
- Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma.Cell reports. Medicine · 2025Article
- DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits.Molecular cancer therapeutics · 2025Article
- Quantitation of the DNA-dependent protein kinase inhibitor peposertib (M3814) and metabolite in human plasma by LC-MS/MS.Biomedical chromatography : BMC · 2024Article
- Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts.Molecular cancer therapeutics · 2024Article
- Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma.Molecular cancer therapeutics · 2024Article
- Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors.The Journal of pharmacology and experimental therapeutics · 2023Article
- Biodistribution of Agmatine to Brain and Spinal Cord after Systemic Delivery.The Journal of pharmacology and experimental therapeutics · 2023Article
- Advances in molecular targeted therapies to increase efficacy of (chemo)radiation therapy.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2023Review
- How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors.Pharmaceutical research · 2023Review
- Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors.The Journal of pharmacology and experimental therapeutics · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Cytotoxic effects of chemotherapy and radiation therapy (RT) used for the treatment of brain metastases results from DNA damage within cancer cells. Cells rely on highly evolved DNA damage response (DDR) pathways to repair the damage caused by these treatments. Inhibiting these repair pathways can further sensitize cancer cells to chemotherapy and RT. The catalytic subunit of DNA-dependent protein kinase, in a complex with Ku80 and Ku70, is a pivotal regulator of the DDR, and peposertib is a potent inhibitor of this catalytic subunit. The characterization of central nervous system (CNS) distributional kinetics of peposertib is critical in establishing a therapeutic index in the setting of brain metastases. Our studies demonstrate that the delivery of peposertib is severely restricted into the CNS as opposed to peripheral organs, by active efflux at the blood-brain barrier (BBB). Peposertib has a low free fraction in the brain and spinal cord, further reducing the active concentration, and distributes to the same degree within different anatomic regions of the brain. However, peposertib is heterogeneously distributed within the metastatic tumor, where its concentration is highest within the tumor core (with disrupted BBB) and substantially lower within the invasive tumor rim (with a relatively intact BBB) and surrounding normal brain. These findings are critical in guiding the potential clinical deployment of peposertib as a radiosensitizing agent for the safe and effective treatment of brain metastases. SIGNIFICANCE STATEMENT: Effective radiosensitization of brain metastases while avoiding toxicity to the surrounding brain is critical in the development of novel radiosensitizers. The central nervous system distribution of peposertib, a potent catalytic subunit of DNA-dependent protein kinase inhibitor, is restricted by active efflux in the normal blood-brain barrier (BBB) but can reach significant concentrations in the tumor core. This finding suggests that peposertib may be an effective radiosensitizer for intracranial tumors with an open BBB, while limited distribution into normal brain will decrease the risk of enhanced radiation injury.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.