Researchers have identified a molecule with the potential to fight triple-negative breast tumors – the most aggressive breast cancer subtype with a less promising prognosis and few effective therapies.
Through laboratory experiments and bioinformatics analyses, the researchers found that the molecule called MS023 induces the tumor cell to self-destruct as it activates one of the cellular defense systems, the interferon system.
Understanding how this molecule works opens up a new perspective to guide future treatments for this subtype of breast cancer.
The study, published on Monday (16) in journal Nature Chemical Biologyhad the participation of researchers from Canada, Brazil, China and the United States, and with the support of the Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp).
“Knowing the stages that are being affected in cells during cancer is essential for both the scientific community and pharmaceutical companies to be able to accelerate strategies for the development of new drugs”, says Katlin Massirer, researcher at the Center for Medicinal Chemistry (CQMED) from the State University of Campinas (Unicamp) and one of the authors of the article.
Breast cancer is the most diagnosed cancer worldwide. The triple negative subtype represents between 15% and 20% of cases and is responsible for 25% of deaths. The recurrence rate is considered high (more than 30%) and survival is very low after metastatic recurrence.
This type of tumor is characterized by the absence – in the tumor cell membrane – of estrogen, progesterone and human epidermal growth factor 2 (HER2) receptors, proteins that classify the other subtypes of breast cancer.
The identification of the type of receptor present in the tumor cell is fundamental for the definition of the treatment – which is more limited in the case of triple negative breast cancer.
In the work, the researchers characterized protein methyltransferase 1 (PRMT1) as a good therapeutic target, found an antitumor molecule and clarified its mode of action.
Then they tested in a laboratory environment (in vitro) 36 compounds that bind to PRMT1, considered a regulator of cell proliferation in triple negative breast cancer. Of these, 15 molecules had a good performance in reducing the tumor, and the MS023 molecule, reported in the study, was the one that presented the best result.
The next experiment was to inoculate mice with triple negative human breast cancer cells. As soon as the animals showed symptoms of the disease, they were treated with the MS023 molecule. The result was a deceleration of tumor advancement in rodents.
The same application was made in organoids, more complex cell structures in the laboratory, derived from tumor cells from cancer patients. In this system, cells self-organize in a three-dimensional way, simulating rudimentary mini-organs. The result in this model was also tumor retraction.
Confirming the hypothesis that the inhibitor molecule was acting on tumor cells, the researchers sought to discover the cellular mechanisms affected by the compound. At this stage, bioinformatics analyzes of the tumor cells were performed and it was found that those treated with MP023 had the most active interferon defense system.
“In healthy people, PRMT1 causes stretches of DNA to be read or protected according to the body’s needs, in tune with the production of important proteins in cells,” explains Katlin, who began studying the topic 25 years ago. .
“However, in the presence of MS023, reading some regions of the genome activates the interferon system as a result of the decrease in PRMT1. The activation of this defense can lead the sick cell to self-destruction”, says Felipe Ciamponi, a Fapesp master’s grantee and co-author of the article.
The Brazilian group worked mainly in bioinformatics analyzes that helped to identify regions of the genome affected during treatment with the molecule, a mechanism that is still poorly understood in cancer.
“There are hundreds of thousands of events happening simultaneously in a cell and finding the effects of the chemical inhibitor is a challenge,” reports Ciamponi. They focused on 560 cellular RNA reading events that involved the tumor inhibition mechanism and it was possible to observe the relationship with the general defense system, the interferon system.
In addition, the group identified activation of the interferon system as a biomarker of cells, which can help doctors know whether or not a given patient will be responsive to certain treatments.
“We’ve taken an important step towards ‘precision medicine,’ where patients are treated with drugs tailored to their specific type of cancer,” says Cheryl Arrowsmith, co-author of the study and a researcher at the Princess Margaret Cancer Center in Canada.
The investigation was carried out within the framework of the Structural Genomics Consortium (SGC), an international consortium of research centers that is a partner of Fapesp in the CQMED project and whose objective is to study underexplored human proteins that can serve as a target for new therapies.
SGC research follows the open science model. Therefore, all the information produced – such as articles, databases, cell lines, a bank of molecules – is freely accessible to researchers in the public or private sector.
Source: CNN Brasil
