The work, led by Vanessa Gottfredi-Head of the Cell Cycle and Genomic Stability Laboratory at FIL and Gaston Soria, former researcher at Consett Sibisi in Córdoba and current CSO of the company OncoPrecision, was recently published in the journal eLife, reported today in CyTA-Leloir. agency.
5% to 10% of hereditary breast cancers and 15% of ovarian cancers are caused by mutations in the BRCA1 and BRAC2 genes, whose function is to repair damaged DNA.
In advanced cases, patients must complement surgery with chemotherapy (eg, cisplatin), although the disease is usually cured after some time.
Current therapeutic options are the so-called PARP inhibitors, which allow longer treatment with fewer side effects, but these drugs are also showing resistance phenomena.
On their way to finding alternatives, a group of Argentinian researchers tracked down molecules capable of neutralizing cells deficient in BRAC2 and, as they published in the journal eLife, the most widely used drug-resistant tumor. Found a new way to stop progress.
Although they did so in experiments on cells in culture, the discovery opens the door to a potentially new generation of drugs.
“We identified an inhibitor of Rho kinase (known as ROCK), the enzyme that regulates the cell skeleton during the final stages of cell division, when two daughter cells are to be produced from one cell. is,” explained CyTA-Leloir Agency Doctor in Human Biology Vanessa Gottifredi.
And he added: “Since BRCA2 also participates in this mechanism of shutting down cell division, tumors deficient in functionality of BRCA2 treated with ROCK inhibitors would lose two key functions that act as backups to each other.” Thus, tumor cells are no longer able to complete cell division successfully and their proliferation is stopped.
On the other hand, the remaining cells of the patient retain functional BRCA2 and can successfully withstand pharmacological inhibition of ROCK.
This principle, which seeks to generate selective death of tumor cells by taking advantage of their genetic alterations, is known as “synthetic lethality” and is aimed at developing “selective toxicity” therapies; That is, they target only cancer cells with mutations that are not present in healthy people. This minimizes adverse side events for the patient.
The expert also pointed out that the work describes several pieces of evidence that ROCK inhibitors use a different mechanism of action than cisplatin or PARP inhibitors, with which they could be presented as candidates for tumor treatment. which accumulate resistance to first and second hand drugs. second line of attack
“Even if ROCK inhibitors are not suitable in the clinic, this finding indicates that it may be possible to continue to find evaluable therapeutic options to prevent excessive proliferation of tumors that are resistant to conventional treatments,” Gottifredi said. Insisted.
Pointing to a limitation of the discovery in which FIL researchers Sebastian Sirie and Julieta Martino also participated as lead authors, Gottfredi noted that the experiments were done on cells in culture and would have to be validated in mice and then , eventually, has to comply. With all phases of clinical trials.
The discovery is the result of years of work by Argentine researchers, who collaborated with scientists from the company GlaxoSmithKline (GSK), and also received funding from the GSK Trust in Science program and the Argentine Ministry of Science and Technology.
