2023-06-01 14:45:48
Between 5 and 10 percent of hereditary breast cancers and 15 percent of ovarian cancers are due to mutations in the BRCA1 and BRAC2 genes, whose function is to repair damaged DNA. In advanced cases, patients must supplement surgery with chemotherapy (for example, cisplatin), although after a while the disease usually recurs. Therefore, the current therapeutic option is the so-called PARP inhibitors, which allow prolonged treatment with fewer side effects. But since these drugs are also showing resistance events, it is necessary to search for new alternatives with different mechanisms of action.
Following this path, in Argentina a group of researchers led by Vanesa Gottifredi, from the Fundación Instituto Leloir (FIL), and Gastón Soria, from the Center for Research in Clinical Biochemistry and Immunology (CIBICI) dependent on the National Council for Scientific and Technical Research ( CONICET), tracked molecules capable of neutralizing cells deficient in BRAC2 and has found a novel way to contain the advance of tumors resistant to the most widely used drugs. Although the researchers did so in experiments with cells in culture, the finding opens the door to a possible new generation of drugs.
“We identified an inhibitor of the Rho kinase (known as ROCK), which is the enzyme that controls the skeleton of the cell during the final stage of cell division, when two daughter cells have to be produced from one cell,” he explained to the CyTA-Leloir Agency, Vanesa Gottifredi, PhD in Human Biology, head of the Cell Cycle and Genomic Stability Laboratory of the Leloir Institute Foundation (FIL). “Since BRCA2 also participates in this mechanism of closure of cell division, the tumor deficient in the functionality of BRCA2 treated with ROCK inhibitors would lose two key functions that serve as backup for each other. Then, the tumor cells cannot successfully complete cell division and their proliferation slows down”, added the author responsible for the work together with Gastón Soria, a former CONICET researcher at the Clinical Biochemistry and Immunology Research Center (CIBICI) in Córdoba. and current CSO of the company OncoPresicion.
Vanesa Gottifredi and Sebastian Siri, of the research team. (Photo: CyTA-Leloir Agency)
On the other hand, the rest of the patient’s cells retain functional BRCA2 and can successfully face the pharmacological inhibition of ROCK. This principle, which seeks to generate selective death of tumor cells by taking advantage of their genetic changes, is known as “synthetic lethality” and aims to develop “selective toxicity” therapies; that is, they target only cancer cells with mutations that are not present in healthy ones. This decreases adverse side events for the patient.
“This function of ROCK in the final stage of cell division may be the key to the selective lethal effect for BRCA2-deficient cells,” specified Gottifredi, who recalled that synthetic lethality is based on the principle that two genetic abnormalities in the same cell causes it to die.
The specialist 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 to treat tumors that accumulate resistance to first- and second-hand drugs. second line of attack “Even if ROCK inhibitors are not suitable for clinical activity, this discovery indicates that it is possible to continue finding evaluable therapeutic alternatives to prevent excessive amplification of tumors resistant to conventional treatments,” Gottifredi emphasized.
When pointing out a limitation of the finding in which the FIL researchers Sebastián Siri and Julieta Martino also participated as main authors, Gottifredi mentioned that the experiments were carried out on cells in culture and that they must be validated in mice and then, finally, comply with all stages of clinical trials. “That puts a distance with the patients; the decisions of whether or not to advance a drug towards its evaluation in people exceed the investigation in the laboratory because of the investment of time and money that they require ”she recognized. And he clarified that this study provides proof of concept, which can invite other scientists to go deeper and try to obtain results that go further.
However, he immediately highlighted an encouraging piece of information: ROCK inhibitors are already used to treat patients with cerebral vasospasm and ischemia and glaucoma, and their activity is being evaluated in clinical trials for other pathologies, which has shown that they can be used in humans. “This could generate interest among pharmaceutical companies already on the market and motivate them to move faster,” she said.
The finding is the result of years of work by Argentine researchers who have 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. “The participation of companies in the development of research together with academic laboratories is a very effective way to achieve progress. We hope that our case will serve as an example for other companies to seek collaborations of this type”, Gottifredi closed.
The study is titled “Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells”. And it has been published in the academic journal eLife. (Source: CyTA-Leloir Agency)
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