A study conducted by researchers from Brazil, Australia, Austria and the United States has advanced the understanding of a type of pediatric cancer without pharmacological treatment options and with a low survival rate. The results, published in the journal Neuro-Oncology, pave the way for the search for more specific therapies.
“The so-called ependymomas are very heterogeneous central nervous system tumors and without many treatment options besides surgery and radiotherapy. Our study focused on the so-called supratentorial ependymoma with fusion between genes C11orf95 and REL [ST-RELA, na sigla em inglês]a frequent subgroup in the pediatric population, aggressive, with a poor prognosis and without specific treatment”, explains Taciani de Almeida Magalhães, first author of the study, carried out during her doctorate at the Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP ) with support from Fapesp.
The work is part of a Thematic Project coordinated by Luiz Gonzaga Tone, a professor at FMRP-USP, who supervised the doctoral research and is one of the co-authors of the article.
This type of ependymoma mainly affects children aged around 8 years (at the time of diagnosis). The five-year survival rate after treatment is approximately 30%, particularly in patients in whom total removal of the tumor through surgery is not possible.
There are no specific drugs and, therefore, the only therapeutic option available besides surgery is radiotherapy, which can cause serious cognitive and motor sequelae in children.
The researchers discovered, with the help of different techniques, that in this tumor the so-called Hedgehog (Hh) cell signaling pathway is highly activated. Therefore, in the laboratory, 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 the treated tumors, however, the researchers observed that they lost certain structures known as primary cilia and, as a result, became resistant to the drug. It was necessary to bring the eyelashes back.
Back on the bench, the group found that cilia formation was regulated by a specific protein, AURKA. Not by chance present in other tumors, the protein also had a specific inhibitor in clinical trials, Alisertib.
In addition to Sonidegib, the researchers then started to treat the tumors with Alisertib. The primary cilia were not lost and Sonidegib was able to act, successfully promoting the death of tumor cells, without affecting healthy ones.
With the drug combination working in the model in vitro, it was up to the researchers to carry out the tests on animals, through a collaboration with scientists from Australia. Mice that developed the brain tumor were treated with the combination. To the researchers’ surprise, however, the animals had no increase in survival compared to control mice, which received no treatment.
The group believes that the layer that covers the blood vessels of the brain to protect them from the external environment, the so-called blood-brain barrier, is preventing the drug from reaching the site to be treated.
“Other studies show that inhibitors of the AURKA protein, the one that promotes the loss of primary cilia, do not reach the brain. It is a possible explanation for the fact that our treatment did not work in animals”, explains Magalhães, who is currently undergoing an internship postdoctoral fellow at Harvard Medical School, in the United States. Before, the researcher had completed part of her doctorate at the same institution.
Alternatives
Now, researchers are looking for other drugs with the same action that can overcome the blood-brain barrier and, who knows, finally get closer to an unprecedented treatment for these tumors.
“Even though the combination did not reach the expected success in the animal model, we now know the molecular mechanisms of the tumor and, therefore, we have a way forward that was not known until then”, says the researcher.
For Elvis Terci Valera, a postgraduate professor at the FMRP-USP Child and Adolescent Health Program, who also collaborated with the study, the discovery opens perspectives for clinical studies using more modern generations of drugs that inhibit the Hh pathway and AURKA protein, with better penetration into the central nervous system.
“Another strategy would be to apply these more modern drugs directly to the cerebrospinal fluid, fluid that circulates in the brain and spinal cord. Options like this could be evaluated in order to reverse treatment resistance”, concludes Valera.
The study Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma 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 the Creative Commons CC-BY-NC-ND license.