A study conducted by researchers in Brazil, Australia, Austria and the United States has made important discoveries about a type of pediatric cancer with no approved drugs for its treatment and with a low survival rate. The findings described in an article published in the journal neuro-oncology pave the way for the search for more specific therapies.
Ependymomas are central nervous system tumors of various types that can basically only be treated by surgical removal and radiation therapy. Our study focused on supratentorial ependymoma with gene fusion C11orf95 other RELATED [ ST-RELA ], a common subgroup in children. It is aggressive, with a poor prognosis and without specific treatment.”
Taciani de Almeida Magalhães, first author of the article
The study was conducted during his doctorate at the Ribeirão 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 Luiz Gonzaga Tone, professor at FMRP-USP. Tone is Magalhães’s thesis advisor and penultimate author of the article.
Ependymoma is the third most common form of childhood brain and spine tumor, occurring primarily in infants and young children. It begins in the ependymal cells that line the hollow cavities within the brain (ventricles) that are 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 around 30%, especially when complete surgical removal of the tumor is impossible. Radiation therapy can cause serious 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 tumors in the laboratory 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 loss of primary cilia, making them resistant to the drug. Primary cilia are organelles made up of microtubules that protrude from the cell membrane into the interstitial space and communicate with the extracellular environment. They are essential for neurological development.
The researchers discovered that the formation of primary cilia was regulated by a specific protein called AURKA. This protein is present in other tumors and had previously been inhibited by alisertib in clinical trials. Therefore, they treated the tumors with alisertib and sonidegib. The primary cilia were no longer lost and Sonidegib was able to act, killing tumor cells without harming healthy cells.
With the drug combination working 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 ependymoma mice treated with the combination was not increased 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 have shown that inhibitors of AURKA, the 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 Magalhães, who is currently in an internship postdoctoral at Harvard Medical School in the United States. He had previously carried out part of his doctoral research at the same institution with a grant from FAPESP.
alternatives
The researchers are now looking for other drugs with the same action that can penetrate the blood-brain barrier, which could lead to the treatment of 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 we have a route to follow that was previously unknown,” said Magalhães.
For Elvis Terci Valera, professor at the FMRP-USP child health program and last author of the article, the discoveries open up the prospect of clinical studies using a more advanced generation of Hh and AURKA inhibitors capable of penetrating the central nervous system.
“Another strategy would be to apply these newer 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 treatment resistance,” Valera said. she said she.