Study reveals mechanism of rare childhood brain cancer;  understand

Study reveals mechanism of rare childhood brain cancer; understand

A study conducted by researchers from Brazil, Australia, Austria and the United States advanced the understanding of a type of childhood cancer without drug treatment options and with a low survival rate. The findings, published in the journal Neuro-Oncology, paved the way for the search for more specific treatments.

“So-called ependymomas are very heterogeneous tumors of the central nervous system and without many treatment options besides surgery and radiotherapy. Our study focused on so-called supraventricular ependymomas with gene fusions. C11orf95 And the RELE [ST-RELA, na sigla em inglês]Taciani de Almeida Magalhães, first author of the study, which she conducted while she was completing her doctorate at Ribeirão Preto School of Medicine, University of São Paulo (FMRP-USP) with support from Fapesp, explains.

The work is part of a thematic project coordinated by Luiz Gonzaga Tone, Professor at FMRP-USP, who supervised the doctoral research and is one of the article’s co-authors.

This type of ependymoma mainly affects children who are about 8 years old (at the time of diagnosis). The five-year survival rate after treatment is close to 30%, particularly in patients whose tumor cannot be completely removed through surgery.

There are no specific medications and, therefore, the only treatment option available besides surgery is radiotherapy, which can cause serious cognitive and motor sequelae in children.

The researchers discovered, with the help of various techniques, that in this tumor the so-called Hh cell signaling pathway is activated. So, in the lab, they treated tumors with Sonidegib – a drug that inhibits the Hh pathway and is currently in clinical trials for other types of cancer that affect the central nervous system.

When evaluating treated tumors, the researchers noted that they had lost some structures known as primary cilia and, as a result, had become resistant to the drug. It was necessary to return the eyelashes.

Back on the bench, the group found that cilia formation is regulated by a specific protein, AURKA. Not coincidentally found in other tumors, the protein also had a specific inhibitor in clinical trials, Alisertib.

In addition to Sonidegib, researchers then began treating tumors with Alisertib. Primary cilia were not lost and Sonidegib was able to function, successfully leading to the death of cancer cells, without affecting healthy cells.

With combination drugs that act in the form in the laboratoryIt was up to the researchers to run the tests on animals, by collaborating with scientists from Australia. Mice that developed a brain tumor were treated with this group. But, to the researchers’ surprise, the animals did not see an increase in the survival rate compared to mice that did not receive any treatment.

The group believes that the layer that covers the brain’s blood vessels to protect them from the external environment, the so-called blood-brain barrier, prevents the drug from reaching the site to be treated.

“Other studies show that inhibitors of the AURKA protein, which promotes the loss of primary cilia, do not reach the brain. It is a possible explanation for the fact that our treatment has not worked in animals,” explains Magalhaes, who is currently a postdoctoral fellow at Harvard Medical School in the United States. The researcher had previously completed part of her Ph.D. at the same institution.

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Now, researchers are looking for other drugs with the same action that can overcome the blood-brain barrier, and who knows, finally approaching an unprecedented treatment for these tumors.

“Although the combination did not reach the expected success in the animal model, we now know the molecular mechanisms of tumorigenesis and, therefore, have a path forward that was not known until then,” says the researcher.

For Elvis Terci Valera, FMRP-USP Graduate Professor of Child and Adolescent Health, who also collaborated with the study, the discovery opens avenues for clinical studies using more recent generations of drugs that inhibit the Hh pathway and the AURKA protein, while improving penetration into the central nervous system.

Valera concludes, “Another strategy is to apply these newer drugs directly to cerebrospinal fluid, the fluid that circulates in the brain and spinal cord. Options like this can be evaluated in order to reverse treatment resistance.”

the study Activation of Hedgehog signaling by endogenous RELA fusion reveals an underlying cilia-dependent impairment in supraventricular ependymoma. It can be read at: https://academic.oup.com/neuro-oncology/advance-article-abstract/doi/10.1093/neuonc/noac147/6596001.

This text was originally published by Agência FAPESP under a Creative Commons CC-BY-NC-ND license. Read the original text here.

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