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Candidate therapeutic drug identified for aggressive childhood brain tumour

A recent study identified fenretinide as a potential therapeutic, showing it can penetrate the barrier, induce tumor cell death, and improve survival in animal models.

Published on the 27 March 2025 by Dr. Christie Foster
Medical Hospital: Neurologist and Neurosurgeon Talk, Use Computer, Analyse Patient MRI Scan, Diagnose Brain. Health Clinic Lab: Two Professional Physicians Look at Functoning CT Scan Find Treatment

Diffuse Midline Glioma (DMG)Ìýis a type of malignant, aggressive brain tumour that mostly affects children, and has a poor prognosis of <2 years survival post-diagnosis for the majority of patients.Ìý

Currently, there are very few effective treatments for this disease. Surgery is usually not an option, and radiotherapy gives only temporary benefits. Clinical efficacy has been unsuccessful in trials of many drugs targeting known DMG mutations, which is likely due to their inability to cross the blood-brain barrier to the tumour site.

In a new study,ÌýUpton et al.Ìýconducted high-throughput screening and validation of a diversity of clinically approved drugsÌýin vitroÌýagainst DMG primary cell cultures, looking for cytotoxic effects specific to tumour cells.Ìý

They identified 6 candidate compounds, of which only 1 was confirmed to effectively penetrate the blood-brain barrierÌýin vivoÌýwhen tested in DMG mouse models: ‘fenretinide’.

As part of the investigation into the antitumour mechanism of this drug in DMG,ÌýRNAÌýwas extracted from cell cultures treated with fenretinide to determine its effect on theÌýtranscriptomeÌý(changes in gene expression).

°Õ³ó±ðÌýRamaciotti CentreÌý±è±ð°ù´Ú´Ç°ù³¾±ð»åÌýRNA quality assessment,ÌýLibrary Preparation, Normalisation and Pooling, followedÌýbyÌýRNA sequencingÌýon a NovaSeq 6000 sequencer.Ìý

RNA-seqÌýshowed that fenretinide upregulates the endoplasmic reticulum stress and Unfolded Protein Response pathways and downregulates neurogenesis. Additional techniques showed that the drug increases the production of reactive oxygen species, inhibits oncogenic pathways, and induces apoptosis (cell death).

°Õ³ó±ðÌýsurvivalÌýof DMG model animals wasÌýsignificantly increasedÌýwhen treated with fenretinide.

This drug is a promising potential therapeutic for patients with DMG.

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Access the publicationÌý.

Upton, D.H., Liu, J., George, S. M., Valvi, S., Ung, C., Rayner, B. S., Gopalakrishnan, A., Pandher, R., Khan, A., Venkat, P., Mayoh, C., Holliday, H., Yeung, N., Nguyen, H., Franshaw, L., Ehteda, A., Shen, H., Farrugia, G., Orienti, I., Reynolds, C. P., Tsoli, M., & Ziegler, D. S. (2025). High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic.ÌýNeuro-Oncology, noaf035.