Evidence map›Paper›PMID 37827699›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2023

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

Wenqiu Zhang, Ju-Hee Oh, Wenjuan Zhang, Sneha Rathi, Jon D Larson, Robert J Wechsler-Reya, Rachael W Sirianni, William F Elmquist

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
1.2field-weighted citation impact, top 19% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 4 citations in OpenAlex.

  1. Central nervous system distributional kinetics of selected histone deacetylase inhibitors.The Journal of pharmacology and experimental therapeutics · 2025
    Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Wenqiu ZhangDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.) elmqu011@umn.edu zhan4937@umn.edu.
Ju-Hee OhDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
Wenjuan ZhangDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
Sneha RathiDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).ORCID 0000-0002-4631-0085
Jon D LarsonDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
Robert J Wechsler-ReyaDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
Rachael W SirianniDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
William F ElmquistDepartment of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.) elmqu011@umn.edu zhan4937@umn.edu.
University of Minnesota · US

Funding

Therapy Evaluation CoreU19CA264362 · NCI · MAYO CLINIC ROCHESTER · PI PARNEY, IAN F · 2021 to 2025
$7.6M
Intrathecal delivery of radiation sensitizing nanoparticles in pediatric neuro-oncologyR01HD099543 · NICHD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SIRIANNI, RACHAEL W · 2019 to 2023
$3.5M
Exploiting sex-dependent brain injury response for nanoparticle therapeuticsR01NS116657 · NINDS · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · PI SIRIANNI, RACHAEL W, STABENFELDT, SARAH E · 2021 to 2025
$2.5M
Targeting Leptomeningeal Metastasis in MedulloblastomaR01NS111292 · NINDS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SIRIANNI, RACHAEL W · 2019 to 2024
$2.4M
NCI NIH HHS U19 CA264362NICHD NIH HHS R01 HD099543NINDS NIH HHS R01 NS111292NINDS NIH HHS R01 NS116657
6 · The paper itself

Abstract

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-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, 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 P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient 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 STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. 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 preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.

Indexed as

ATP-Binding Cassette TransportersBrain NeoplasmsAnimalsATP Binding Cassette Transporter, Subfamily BATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Blood-Brain BarrierBrainCentral Nervous SystemChildHumansMembrane Transport ProteinsMiceNeoplasm ProteinsPanobinostatATP-Binding Cassette TransportersATP Binding Cassette Transporter, Subfamily BATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Membrane Transport ProteinsNeoplasm ProteinsPanobinostat

Identifiers

PMID37827699
PMCPMC10658912
OpenAlexW4387581908

What OpenQuestion holds

Textmetadata
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Registered trials

None linked

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.