A study by researchers from Brazil, Australia, Austria and the United States has made significant discoveries about a type of childhood cancer that has no approved treatment and has a low survival rate. The findings are described in an article published in the journal Neuro-oncology pave the way for finding more specific treatments.
“Ependymomas are tumors of the central nervous system of various types that can mostly be treated only by surgical removal and radiation therapy. Our study focused on supratentorial ependymoma with a fusion of the C11orf95 and RELA genes [ST-RELA], a subgroup common in children. It is aggressive, with a poor prognosis and no specific treatment,” said Taciani de Almeida Magalhães, first author of the paper. The study was conducted during her doctoral work at the Ribeirao Preto School 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 Luis Gonzaga Tone, professor at FMRP-USP. Thon is Magallanes' thesis supervisor and penultimate author of the paper.
Ependymoma is the third most common form of childhood brain and spinal cord tumor, occurring mostly in infants and young children. It begins in the ependymal cells that line the hollow cavities of the brain (ventricles) filled with cerebrospinal fluid. Supratentorial refers to the upper part of the brain. Supratentorial ependymoma mainly affects children around 8 years of age at the time of diagnosis. The five-year survival rate is about 30%, especially where complete surgical removal of the tumor is not possible. Radiation therapy can cause severe cognitive and motor complications.
Using a series of advanced techniques, the researchers discovered that the so-called Hedgehog (Hh) signaling pathway is highly activated in this type of tumor. They treated the tumors in the lab with sonidegib, an Hh inhibitor that is currently in clinical trials as a drug for other central nervous system tumors.
Analysis of the treated tumors showed a loss of primary cilia, making them resistant to the drug. Primary cilia are organelles consisting of microtubules that protrude from the cell membrane into the interstitial space and communicate with the extracellular environment. They are important for neurological development.
Researchers have found that the formation of primary cilia is regulated by a specific protein – called AURKA. This protein is present in other tumors and was previously inhibited by Alisertib clinical trials . So they treated the tumors with Alisertib as well as Sonidegib. Primary cilia were no longer lost, and sonidegib was able to act by killing tumor cells without damaging healthy cells.
The drug combination worked well in an in vitro model, then they tested it in animals in collaboration with a research group in Australia. To their surprise, the survival rate of mice with ependymoma that received the combination did not increase compared to untreated mice used as controls.
The researchers believe that the blood-brain barrier may have prevented the drugs from reaching the tumors. “Other studies showed that inhibitors of AURKA, a protein that contributes to primary cilia loss, did not reach the brain. This is a possible explanation for the failure of our treatment of animals,” said Magallians, who is currently on a post-graduate internship. at Harvard Medical School in the US. She previously spent part of her Ph.D. studies at the same institution with a FAPESP scholarship.
Alternatives
Researchers are now looking for other drugs with the same effect 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 a tumor “Molecular mechanisms and there is a route to follow that was previously unknown,” said Magaljainsh.
For Elvis Tursey Valerie, a professor in the FMRP-USP Child Health Program and last author of the paper, these findings open the door to clinical trials using a more advanced generation of Hh and AURKA inhibitors capable of penetrating the central nervous system.
“Another strategy would be to apply these more advanced drugs directly into the cerebrospinal fluid, which is produced by ependymal cells in the ventricles of the brain, and in the spinal cord. Such options could be evaluated as a way to eliminate resistance to treatment,” Valera said.
Additional information:
Taciani de Almeida Magalhães et al. Activation of Hedgehog signaling by an oncogenic RELA fusion reveals primary cilia-dependent vulnerability of supratentorial ependymoma, Neuro-oncology DOI: 10.1093/neuonc/noac147
Citation : Study reveals mechanism linked to rare childhood brain cancer, points to possible treatment (29 Aug 2022) Retrieved 29 Aug 2022 from https://medicalxpress.com/news/2022-08-reveals-mechanism -involved-rare-pediatric. html
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