Diffuse Midline Glioma (DMG) is 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. 

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, Upton et al. conducted high-throughput screening and validation of a diversity of clinically approved drugs in vitro against DMG primary cell cultures, looking for cytotoxic effects specific to tumour cells. 

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

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

The Ramaciotti Centre performed RNA quality assessment, Library Preparation, Normalisation and Pooling, followed by RNA sequencing on a NovaSeq 6000 sequencer. 

RNA-seq showed 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).

The survival of DMG model animals was significantly increased when treated with fenretinide.

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

Access the publication here.

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. Neuro-Oncology, noaf035.

News article written by Dr. Christie Foster