A group of researchers from Canada, Brazil and the United States identified two molecules with the potential to treat glioblastoma, one of the most aggressive types of brain cancer, with a survival rate of less than 10%.
The molecules act specifically on tumor stem cells, which have an important relationship with resistance to treatments. According to the researchers, few compounds are able to act on this type of cell, which exists in small amounts in tumors.
The study, published in Nature Communications, was carried out within the scope of the Structural Genomics Consortium (SGC), which has as partner in Brazil the Center for Medicinal Chemistry of the State University of Campinas (CQMED-Unicamp), supported by FAPESP.
The two molecules act on the same protein, but have different mechanisms of action on the tumor. Since it is a disease with few treatment options, it is necessary to work with the possibility of a combined therapy, which would attack the tumor on different fronts. Our work increases the understanding of the mechanism of action of these molecules “, explains Katlin Brauer Massirer, a researcher at the Center for Molecular Biology and Genetic Engineering (CBMEG-Unicamp) supported by FAPESP and one of the coordinators of the study.
The compounds – called GSK591 and LLY-283 – inhibit the PRMT5 protein, which acts on the replication of tumor stem cells. In this way, they manage to prevent the tumor from progressing.
“Under normal conditions, this protein [PRMT5] is very important for a cell control process that we call splicing to RNA [processamento do RNA mensageiro para a produção de proteínas]. In glioblastoma, however, the excess of this molecule disrupts this process and favors the growth of the tumor. What these inhibitors do is the physical binding of the PRMT5 protein, preventing it from acting in an unregulated manner “, explains Felipe Ciamponi, Brazilian co-author of the work, carried out during his master’s degree at CBMEG-Unicamp, where he is currently doing a doctorate.
Using bioinformatics tools, Brazilian researchers analyzed hundreds of thousands of data from tumor cells treated with one of the compounds.
The glioblastoma samples used in the experiments were collected from patients seen at three hospitals in Canada.
“Collaboration with the CQMED group was essential for the work. One of the main focuses of the PRMT5 study as a target for drugs was precisely the understanding of splicing. Brazilian researchers helped us to identify the cellular mechanism in action and to make the association with what we observed in patient samples. In addition, Ciamponi identified a new signature in a group of patients that was able to predict the response to the compounds, ” FAPESP Agency Panagiotis Prinos, a researcher at the University of Toronto and one of the study’s coordinators.
Both molecules were shown to be potent against the tumor and non-toxic in healthy cells. Trials in mice with tumors derived from patients’ stem cells showed that LLY-283 can penetrate the so-called blood-brain barrier, a structure that protects the brain from potentially toxic substances. This is an essential factor for a future drug to act on the brain.
Another demonstration of the potential of LLY-283 was the fact that it was administered orally to mice. Treated animals had considerably longer survival than non-medicated animals, showing the effect of the compound even when taken orally.
With the results, new tests will be carried out to understand the importance of the events of splicing under the action of the molecules and to perfect the compounds, so that they can become drugs of clinical use one day.
“Other groups are also researching molecules that target this protein. It is important to say that we were able to identify compounds that are, at the same time, potent and selective when reaching PRMT5 and that these will still be perfected and tested in combination, including with drugs already In addition, this tumor has subtypes that can be very sensitive or resistant to one or the other drug. That is why it is important to have several options “, says Massirer.
Currently, two compounds similar to the study are being tested in the United States, in patients with acute myeloid leukemia, non-Hodgkin’s lymphoma and solid tumors. “We share our results with these research groups and we are interacting with them to include brain tumors in the tests,” says Prinos.
The Unicamp group also plans to include patients from Brazilian hospitals in the project and to attract pharmaceutical companies from the country as partners.
The article PRMT5 inhibition disrupts splicing and stemness in glioblastoma can be read at: www.nature.com/articles/s41467-021-21204-5.
This text was originally published by Agência FAPESP under the Creative Commons license CC-BY-NC-ND.