Evidence map›Paper›PMID 39935375›Full record

ArticleNeuro-oncology2025

High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.

Dannielle H Upton, Jie Liu, Sandra M George, Santosh Valvi, Caitlin Ung, Benjamin S Rayner, Anjana Gopalakrishnan, Ruby Pandher, Aaminah Khan, Pooja Venkat and 12 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
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

22 authors.

Dannielle H UptonSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Jie LiuChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Sandra M GeorgeChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Santosh ValviChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0002-9655-0001
Caitlin UngChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Benjamin S RaynerSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Anjana GopalakrishnanChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Ruby PandherSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Aaminah KhanSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Pooja VenkatChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Chelsea MayohSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Holly HollidaySchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.
Nicole YeungChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Hieu NguyenChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Laura FranshawChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Anahid EhtedaChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Han ShenChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0003-2435-2150
Giovanna FarruggiaAlma Mater Studiorum University of Bologna, Department of Pharmacy and Biotechnology, Bologna, Italy.
Isabella OrientiAlma Mater Studiorum University of Bologna, Department of Pharmacy and Biotechnology, Bologna, Italy.
C Patrick ReynoldsCancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Maria TsoliSchool of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia.ORCID 0000-0003-1155-0510
David S ZieglerKid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.

Funding

Cure Brain Cancer FoundationNational Health and Medical Research Council 2019056
6 · The paper itself

Abstract

backgroundDiffuse midline glioma, characterized by H3K27 alteration (DMG), is the predominant high-grade glioma in children. It commonly originates in the brainstem, yet effective treatments for these patients remain elusive.

methodsTo identify novel therapies for DMG, we conducted high-throughput drug screens (HTS) using biologically active, clinically approved compounds against DMG neurospheres. Multiple primary DMG cultures were utilized in conjunction with in vitro cytotoxicity and clonogenic assays to validate the efficacy of top compounds. Molecularly diverse patient-derived and transgenic DMG orthotopic models were employed to assess therapeutic efficacy alongside pharmacokinetic and immunohistochemical analyses. Mechanistic studies, including RNA sequencing, western blotting, and flow cytometry, were conducted to elucidate the antitumor efficacy of the most promising compound, fenretinide, in DMG cells.

resultsThrough HTS, 6 compounds were identified and validated for their potent cytotoxic activity. However, most of these compounds failed to improve survival in an orthotopic Diffuse Midline Glioma (DMG) model due to limited blood-brain barrier (BBB) penetration. In contrast, fenretinide exhibited effective BBB penetration, significantly enhancing the survival of tumor-bearing animals. Mechanistic studies revealed that fenretinide increased reactive oxygen species (ROS) generation and induced apoptosis by inhibiting PDGFRα. RNA-sequencing further elucidated that fenretinide upregulates the Unfolded Protein Response (UPR) and endoplasmic reticulum (ER) stress pathways while downregulating neurogenesis. The in vivo antitumor efficacy of 2 fenretinide formulations was demonstrated in PDGFRα-amplified and transgenic DMG models.

conclusionThis comprehensive study has identified new DMG therapeutic vulnerabilities and highlights fenretinide as a brain-penetrant, anti-DMG agent.

Indexed as

Antineoplastic AgentsBrain NeoplasmsFenretinideGliomaHigh-Throughput Screening AssaysAnimalsApoptosisBlood-Brain BarrierCell ProliferationDrug Screening Assays, AntitumorFemaleHumansMiceTumor Cells, CulturedXenograft Model Antitumor AssaysAntineoplastic AgentsFenretinideDMGfenretinidehigh-throughput screeningPDXtherapeutic

Identifiers

PMID39935375
PMCPMC12417829

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Registered trials

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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.