A study by researchers in Brazil, Australia, Austria and the United States has made significant discoveries about a type of pediatric cancer with no approved drugs for treatment and 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 radiotherapy. Our study focused on supratentorial ependymoma with fusion of the C11orf95 and RELA genes [ST-RELA], a frequent subgroup in children. It is aggressive, with a poor prognosis and no specific treatment”, explains Taciani de Almeida Magalhães, first author of the article. The study was carried out 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, 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 brain’s empty cavities (ventricles) that are filled with cerebrospinal fluid. Supratentorial refers to the upper part of the brain. Supratentorial ependymoma mainly affects children around 8 years old at the time of diagnosis. The five-year survival rate is approximately 30%, especially when complete surgical removal of the tumor is impossible. 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 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 the loss of primary cilia, making them resistant to the drug. Primary cilia are organelles formed by 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 with Alisertib in clinical trials. So they treated the tumors with Alisertib and with Sonidegib. Primary cilia were no longer lost and Sonidegib was able to act, causing tumor cell death without damaging healthy cells.
With the drug combination working well in the in vitro model, they then tested it in animals, in collaboration with a research group in Australia. To their surprise, the survival rate of ependymoma mice treated with 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 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 postdoctoral internship 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
Researchers are now looking for other drugs with the same action that can penetrate the blood-brain barrier, potentially leading 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 have a route to follow that was previously unknown,” said Magalhães.
For Elvis Terci Valera, a professor in the child health program at FMRP-USP and last author of the paper, the findings open up a perspective for clinical studies with a more advanced generation of Hh and AURKA inhibitors capable of penetrating the system 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 spinal cord. Options like this could be evaluated as a way to reverse treatment resistance,” he said. value
About the São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by granting grants, scholarships and grants to researchers linked to institutions of higher education and research from the state of São Paulo, Brazil. FAPESP is aware that the best research can only be done by working with the best international researchers. It has therefore established partnerships with funding agencies, higher education, private companies and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their col · international collaboration. You can get more information about FAPESP at www.FAPESP.br/en and visit the FAPESP news agency at www.agencia.FAPESP.br/en to keep up to date with the latest scientific advances that FAPESP helps achieve through the its numerous programs, awards and research centers. You can also subscribe to the FAPESP news agency at