ArticleThe Journal of pharmacology and experimental therapeutics2017
Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma.
Article in The Journal of pharmacology and experimental therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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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
21 citing papers in PubMed.
- Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma.Cancer medicine · 2019Trial
- Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations.Nature communications · 2026Article
- Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-Wild-type Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- A Repurposed Drug Selection Pipeline to Identify CNS-Penetrant Drug Candidates for Glioblastoma.Pharmaceuticals (Basel, Switzerland) · 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
- How Much is Enough? Impact of Efflux Transporters on Drug delivery Leading to Efficacy in the Treatment of Brain Tumors.Pharmaceutical research · 2023Review
- ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery.Pharmacological reviews · 2023Review
- Radiation Sensitivity: The Rise of Predictive Patient-Derived Cancer Models.Seminars in radiation oncology · 2023Review
- Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Factors Influencing Luciferase-Based Bioluminescent Imaging in Preclinical Models of Brain Tumor.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Brain Distribution of Berzosertib: An Ataxia Telangiectasia and Rad3-Related Protein Inhibitor for the Treatment of Glioblastoma.The Journal of pharmacology and experimental therapeutics · 2021Article
- A Phase II Study of the Multikinase Inhibitor Ponatinib in Patients With Advanced,JTO clinical and research reports · 2020Article
- Review
- Targeting the Extra-Cellular Matrix-Tumor Cell Crosstalk for Anti-Cancer Therapy: Emerging Alternatives to Integrin Inhibitors.Frontiers in oncology · 2020Review
- Heterogeneous drug tissue binding in brain regions of rats, Alzheimer's patients and controls: impact on translational drug development.Scientific reports · 2019Article
- Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies.OncoTargets and therapy · 2019Review
- Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma.Nature communications · 2018Article
- Review
- Lycorine inhibits glioblastoma multiforme growth through EGFR suppression.Journal of experimental & clinical cancer research : CR · 2018Article
- Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine.Pharmaceutical research · 2018Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC
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