Itaconate identified as a new target for pediatric brain tumors called ependymomas

Ependymomas are tumors that grow in the brain or spinal cord and are the third-most common type of brain tumor in children.

This type of cancer affects about 250 children in the United States each year and is most often diagnosed in children aged eight and younger.

Despite decades of research, the existing treatments only prolong survival and do not cure these tumors.

In a study published in Nature, University of Michigan researchers have found that a specific molecule called itaconate drives the development of ependymomas.

Their findings can help future drug development for children with this type of malignant brain tumor.

More than 80% of ependymomas that arise in the upper part of the brain have a cancer-causing protein fusion named ZFTA-RELA.

Previous studies have shown that neither ZFTA nor RELA can cause cancer on its own, but when the two fuse together, they drive tumor growth.

Cancer cells require large amounts of nutrients to grow, and the researchers worked to identify what metabolic changes occur during this process.

Using animal models and cell lines from mice and patients, they found that ependymomas make the metabolite itaconate.

The finding was unexpected because itaconate is mainly made by immune cells called macrophages in response to invading pathogens.

When the researchers prevented the enzyme aconitate decarboxylase 1, or ACOD1, from producing itaconate in mouse models, they were able to reduce ependymoma tumor growth.

“We were surprised that a brain tumor produces a metabolite that is usually made by immune cells,” said Siva Kumar Natarajan, a postdoctoral research fellow in the Venneti lab.

“We wanted to find out what itaconate was doing in these tumors.”

Using ependymoma cells, the researchers looked at which genes behaved differently when ACOD1 is absent.

They found that itaconate forms a feedback loop with ZFTA-RELA, where they boost each other to promote tumor growth.

This loop relies on the amino acid glutamine that is used as a building block for itaconate synthesis.

When the researchers inhibited this loop, the levels of ZFTA-RELA were reduced and the tumor shrank in mouse models.

“This is the first study to show that the ZFTA-RELA fusion can be targeted in this type of tumor,” said Sriram Venneti, M.D., Ph.D., Professor of Pathology and Pediatrics, member of Rogel Cancer Center and Co-Director of the Chad Carr Pediatric Brain Tumor Center.

“We are hoping to expand this study to protein fusions that function similarly in other types of cancer.”

The researchers are also working with the Pediatric Neuro-Oncology Consortium in developing a clinical trial that can target the itaconate pathway in patients with ependymomas.

Additional authors: Joanna Lum, James Haggerty Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill M. Bayliss, Akash Deogharkar, Erin Taya Hamanishi, Matthew Pun1, Stefan R. Sweha, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Olamide Animasahun, Pranav Narayanan, Sushanth Sunil, Abhijit Parolia, Peter Sajjakulnukit, Pooja Panwalkar, Robert Doherty, Madison Clausen, Derek Dang, Debra Hawes, Fusheng Yang, Mariarita Santi, Alexander R Judkins, Yelena Wilson, Thomas Vigil, Andrea Franson, Richard M Mortensen, Tatsuya Ozawa, Andrea Griesinger, Eric C. Holland, Nicholas K. Foreman, Kulandaimanuvel Antony Michaelraj, Sameer Agnihotri, Michael Taylor, Richard J Gilbertson, Carl Koschmann, Arul M. Chinnaiyan, Costas A. Lyssiotis and Deepak Nagrath.

Funding/disclosures: This work was funded by the Sontag Foundation, Clinical Scientist Development Award - Doris Duke Charitable Foundation, the Hyundai Hope On Wheels Foundation, NINDS R01NS110572, NCI R01CA261926, and the Julie Taubman Reys emerging scholar award from the University of Michigan Taubman Institute. This work was also supported by a fellowship award from The Robert Connor Dawes Foundation/ CERN Foundation: Ependymoma Cancer Research Network/ National Brain Tumor Society. The Venneti lab is/was supported by grants from Mathew Larson, Sidney Kimmel, St Baldrick’s, Claire McKenna, Chad Tough, Alex’s Lemonade Stand, Storm The Heavens and the University of Michigan Chad Carr Pediatric Brain Tumor Initiative. Natarajan was supported by the Momental Foundation and is currently funded by the Michigan Pioneer Fellows Program, the ChadTough Defeat DIPG, Alvin L. Glick Foundation, Alex’s Lemonade Stand Foundation Young Investigator Award – Grant #1454502, and the AACR-SONTAG Foundation Brain Cancer Research Fellowship - #25-40-78-NATA. Koschmann acknowledges the following funding sources National Institutes of Health Grant - R01-NS119231, National Institutes of Health Grant - R01-NS124607, and DOD Grant - CA201129P1. Chinnaiyan acknowledges funding from National Institutes of Health Grant - R35CA231996. Chinnaiyan is a Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar, and American Cancer Society Professor.

Paper cited: “ZFTA-RELA ependymomas produce itaconate to epigenetically sustain pathogenic fusion expression,” Nature. DOI: 10.1038/s41586-025-10005-1

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