A study by scientists from Brazil, Australia, Austria and the United States has made important discoveries about a type of childhood cancer that has no approved cure and has a low survival rate. Findings described in an article published in the journal Neurooncology pave the way for finding more specific treatments.
“Ependymomas are tumors of the central nervous system of various types, which are mainly treatable only by surgical removal and radiation therapy. Our study focused on gene fusion supratentorial ependymoma. C11orf95 as well as RELA [ ST-RELA ], a subgroup frequently found in children. It is an aggressive disease with a poor prognosis and no specific treatment,” said Tasiani de Almeida Magalhães, first author of the paper. The study was conducted during her doctoral research at the Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP) in Brazil. , supported by FAPESP.
The study was part of a thematic project led by Luis Gonzaga Tone, Professor at FMRP-USP. Tone is Magalhães’ Academic Supervisor and penultimate author of the paper.
Ependymoma is the third most common tumor of the brain and spinal cord in children, occurring mainly in infants and young children. It begins in ependymal cells that line hollow spaces in the brain (ventricles) filled with cerebrospinal fluid. Supratentorial refers to the top of the brain. Supratentorial ependymoma mostly affects children around 8 years of age at the time of diagnosis. The five-year survival rate is about 30%, especially when complete surgical removal of the tumor is not possible. Radiation therapy can cause serious cognitive and motor complications.
Using a variety of cutting-edge techniques, the researchers found that the so-called Hedgehog (Hh) signaling pathway is highly upregulated 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 treatment for other central nervous system tumors.
Analysis of the treated tumors showed loss of primary cilia, making them resistant to the drug. Primary cilia are microtubule organelles that protrude from the cell membrane into the interstitial space and communicate with the extracellular environment. They are essential for the development of the nervous system.
The researchers found that the formation of primary cilia is regulated by a specific protein called AURKA. This protein is present in other tumors and has been previously inhibited by Alisertib in clinical trials. So they treated the tumors with Alisertib as well as Sonidegib. Primary cilia were no longer lost and Sonidegib could act to kill tumor cells without any damage to healthy cells.
Because the drug combination worked well in an in vitro model, they then tested it in animals in collaboration with a research team in Australia. Surprisingly, the ependymoma mice treated with the combination did not survive longer than the untreated mice used as controls.
The researchers believe that the blood-brain barrier may have prevented drugs from reaching the tumors. “Other studies have shown that inhibitors of AURKA, a protein that promotes the loss of primary cilia, did not reach the brain. This is a possible explanation for the failure of our treatment in animals,” said Magalhænes, who is currently in postdoctoral fellowship. at Harvard Medical School in the USA. Previously, she did part of her doctoral research at the same institution with a FAPESP fellowship.
Alternatives
Researchers are now looking for other drugs with the same effect that can cross the blood-brain barrier, potentially leading to a first-time treatment for this disease. “While the combination was not successful in our animal model, we now understand the molecular mechanisms of the tumor and are able to follow a path that was previously unknown,” Magalhaines said.
For Elvis Terchi Valera, Professor of the FMRP-USP Child Health Program and the paper’s final author, the findings open up the prospect of clinical research using a more advanced generation of Hh and AURKA inhibitors that can enter the central nervous system.
“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. said.