Discovery paves the way for specific therapies for a common form of childhood brain and spinal tumor


A study by researchers in Brazil, Australia, Austria and the United States has made important findings about a type of childhood cancer without approved drugs for treatment and with a low survival rate. The results, described in an article published in the journal Neuro-oncologypave the way for the search for more specific therapies.

Ependymomas are central nervous system tumors of various types that can essentially only be treated by surgical removal and radiation therapy. Our study focused on supratentorial ependymomas with gene fusion C11orf95 and RELA [ST-RELA], a common subgroup in children. It’s aggressive, with a bad prognosis and without specific treatment.”

Taciani de Almeida Magalhães, first author of the article

The study was conducted during his doctoral research at the Ribeirão Preto Faculty of Medicine of the University of São Paulo (FMRP-USP) in Brazil, with the support of FAPESP.

The study was part of a thematic project led by Luiz Gonzaga Tone, a professor at FMRP-USP. Tone is Magalhães’ thesis supervisor and penultimate author of the paper.

Ependymoma is the third most common form of childhood brain and spinal tumor, occurring mostly in infants and young children. It begins in the ependymal cells lining the hollow cavities of the brain (ventricles) which are filled with cerebrospinal fluid. The supratentorial refers to the upper part of the brain. Supratentorial ependymoma mainly affects children who are around 8 years old at the time of diagnosis. The five-year survival rate is about 30%, especially when complete surgical removal of the tumor is impossible. Radiation therapy can cause serious cognitive and motor complications.

Using a range of advanced techniques, the researchers discovered that the so-called Hedgehog (Hh) signaling pathway is strongly activated in this type of tumour. They treated tumors in the lab with Sonidegib, an Hh inhibitor currently in clinical trials as a drug for other central nervous system tumors.

Analysis of treated tumors showed loss of primary cilia, making them resistant to the drug. Primary cilia are organelles made up of microtubules that extrude from the cell membrane into the interstitial space and communicate with the extracellular environment. They are essential for neurological development.

The researchers found that the formation of primary eyelashes was regulated by a specific protein called AURKA. This protein is present in other tumors and had already been inhibited using Alisertib in clinical trials. So they treated the tumors with Alisertib as well as Sonidegib. The primary cilia were no longer lost, and Sonidegib was able to act, causing tumor cell death without damaging healthy cells.

Since the drug combination worked well in the in vitro model, they then tested it on animals, in collaboration with a research group in Australia. To their surprise, the survival rate of mice with ependymoma treated with the combination did not increase compared to untreated mice used as controls.

The researchers believe that the blood-brain barrier may have blocked the drugs from reaching the tumours. “Other studies have shown that inhibitors of AURKA, the protein that promotes the loss of primary eyelashes, do not reach the brain. This is a possible explanation for the failure of our treatment in animals,” said said Magalhães, who is currently on a postdoctoral fellowship. at Harvard Medical School in the United States. Previously, she had carried out part of her doctoral research in the same institution with a grant from FAPESP.


Researchers are now looking for other drugs with the same action that can cross the blood-brain barrier, potentially leading to a treatment for the disease for the first time. “Although the combination was not successful in our animal model, we now understand the molecular mechanisms of the tumor and have a way forward that was previously unknown,” Magalhães said.

For Elvis Terci Valera, professor in the FMRP-USP child health program and final author of the article, these findings open the prospect of clinical studies using a more advanced generation of Hh and AURKA inhibitors capable of penetrating the nervous system. central.

“Another strategy would be to apply these more modern drugs directly to the cerebrospinal fluid produced by ependymal cells in the ventricles of the brain and to the spinal cord. Options like this could be evaluated as a way to reverse resistance. to treatment,” Valera said. said.


São Paulo Research Foundation (FAPESP)

Journal reference:

Magalhães, T., et al. (2022) Activation of Hedgehog signaling by oncogenic RELA fusion reveals primary cilia-dependent vulnerability in supratentorial ependymoma. Neuro-Oncology.


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