He breast cancer It is the most diagnosed type of cancer in Spain after colon and rectal cancer, according to the Spanish Society of Medical Oncology (SEOM), which estimates that 34,750 new cases will be diagnosed in 2022, which represents 28.9% of the total. cancers in women. About one in seven (15%) of these cases are a very aggressive form of the disease known as triple negative breast cancerwhich is highly resistant to available treatments because its cells lack the receptors targeted by breast cancer drugs.
Now, an experimental treatment that has been tested in mice shows an “exciting” new strategy that could transform triple-negative breast cancer into a controllable disease. Researchers from the Center for Genomic Regulation and the Vall d’Hebron Institute of Oncology have shown that the simultaneous inhibition of two different proteins can represent a new therapeutic strategy against triple negative breast cancer. The findings have been published in EMBO Molecular Medicine.
Recently, it has been shown that the LOXL2 enzyme promotes the development of triple negative breast cancer. A team led by Miss Sara Sdelcifrom the Center for Genomic Regulation, and the Dr. Sandra Peirótogether with the Non-Colorectal Gastrointestinal Cancer Translational Research Group of the Vall d’Hebron Institute of Oncology, has carried out several analyzes to evaluate the suitability of this enzyme as a biomarker to predict the success of treatments.
“We have gone deeper at the molecular level to understand how triple negative breast cancer cells grow and we have discovered a new mechanism that can be exploited for therapeutic purposes”
They found that LOXL2 expression alone predicts the outcomes of drugs that target BRD4, a cancer-promoting protein. These findings prompted the researchers to conduct further experiments to determine whether the LOXL2 and BRD4 proteins could be collaborating to contribute to the proliferation of triple-negative breast cancer cells.
Several experiments demonstrated that LOXL2 interacts with a version of BRD4 within the cell nucleus. The researchers also demonstrated that this interaction modifies the expression of certain genes that contribute to the proliferation of triple-negative breast cancer cells. Inhibiting both proteins at the same time disrupted these interactions and helped slow cancer growth in cell cultures (in vitro) and in three different mouse models (alive).
That triple negative breast cancer is a controllable disease
“We have delved deeper at the molecular level to understand how triple-negative breast cancer cells grow and have discovered a new mechanism that can be exploited for therapeutic purposes. It’s exciting, because a double attack strategy targeting both proteins could be combined with other treatments and transform triple negative breast cancer, going from being a disease with an unfavorable prognosis to one that is controllable,” says Dr. Laura Pascual Reguant, first author of the study and postdoctoral researcher at the Center of Genomic Regulation, in Barcelona.
The findings have important implications for an experimental class of drugs known as BET inhibitors, which have shown promising results in the fight against triple negative breast cancer. BET inhibitors act by compromising the function of BRD4, but have failed to reach the clinic because triple-negative breast cancer cells acquire resistance to treatment. The study authors believe that simultaneous modulation of BRD4 and LOXL2 could help overcome this resistance.
The next challenge will be to find a way to safely and effectively target both proteins at the same time. One possible strategy is to combine different inhibitors. BET inhibitors are already targeting different versions of BRD4 in 30 clinical trials, five of which target triple-negative breast cancer. LOXL2 inhibitors also exist, but their safety and effectiveness in cancer treatment have not been explored.
The combination of both inhibitors has not been tested yet. “More work remains before our findings benefit patients, but any progress in understanding the mechanisms of this highly aggressive disease is good news. As we continue to unravel the mechanisms that explain how triple-negative breast cancer proliferates, the health challenges ahead may be more manageable than we thought,” concludes Dr. Sdelci.
Fuente: Center for Genomic Regulation