A group of Barcelona researchers has identified a key enzyme in the origin of the metastases of some types of breast cancer, which opens the door to developing drugs that help prevent them. The finding, published this Thursday in the journal Nature Cell Biology, has been the result of unraveling the mechanisms by which some patients are more likely than others to suffer the spread of cancer cells to other parts of the body.
The work focuses on women who suffer from breast cancer and whose tumor cells have high levels of a protein called MAF. These patients, approximately one in five affected by breast tumors, have a higher risk of metastasis, and do not benefit from the preventive treatments that are usually administered to prevent cancer cells from jumping to the bones, the so-called bisphosphonates. Quite the contrary, in many cases, especially among younger patients, the prognosis worsens after treatment.
“This discovery represents a critical step in understanding how breast cancer spreads, and opens new therapeutic opportunities for the 20% of patients who cannot benefit from treatment with bisphosphonates,” explains Roger Gomis, researcher at the Institute. of Biomedical Research of Barcelona (IRB) who directed the study.
Scientists have observed, in tests in cell cultures and with mice, that if they block a single enzyme of all the molecules that participate in the metastatic process, the one called KDM1A, cancer cells are reduced in their ability to jump to other organs. To block the enzyme, the IRB team has taken advantage of an inhibitor found independently by other research groups.
The study, in which the Center for Genomic Regulation (CRG), the Sant Joan de Déu hospital, both in Barcelona, and the University of Sheffield, in the United Kingdom, have collaborated, opens up the possibility of developing drugs that prevent metastasis in a group of breast cancer patients especially susceptible to suffering from this complication. In fact, the inhibitor they have used is immersed in a phase two clinical trial for the treatment of acute myeloid leukemia, a type of blood cancer.
If its safety and effectiveness are confirmed, Gomis points out in conversation with La Vanguardia, it may be a good candidate to preventively treat patients with high levels of MAF. Despite everything, the expert is cautious with a hypothetical clinical application, for which there are still many steps left.
The group led by Gomis discovered the relationship between high levels of MAF, the increased risk of metastasis and the poor functioning of bisphosphonate treatment seven years ago. The results led the scientist to found the company Inbiomotion, with which he developed a test to detect patients with high MAF levels. The objective was “to provide information to oncologists about which patients can be treated with bisphosphonates to prevent metastases and which cannot,” details the expert.
Bisphosphonates prevent cancer cells from jumping to the bones, the most common metastatic process in breast cancer. The problem is that in some cases it can divert metastases to other organs, such as the liver or brain, leading to much worse complications. This risk is greater among patients with high levels of MAF, for whom treatment is not recommended.
The test developed by Inbiomotion has already passed two clinical trials, has been on the market for three months in Spain and has been used as a diagnostic tool. The mechanism underlying these associations, however, has remained a mystery to this day.
Now, researchers have unraveled the complex molecular puzzle behind these phenomena. They have seen that when cancer cells have high levels of MAF, the proteins collaborate with a molecule called estrogen receptor, well-known in the oncological field for being responsible for cancer growth in 70% of breast tumors. This interaction restructures the DNA of cancer cells, making them “metastasis machines,” Gomis describes.
By analyzing the molecular mechanism step by step, the team has identified that the KDM1A enzyme is, in the expert's words, “the executing arm” of genomic changes. It is ultimately responsible for these women having a higher metastatic risk. Without it, the researchers hypothesize, the probability of metastasis in women with high levels of MAF should not be increased.
Roger Gomis values the discovery as the culmination of a “virtuous circle” of research, application and new research. “We come from a discovery 7 years ago, which led us to develop a test, which is validated in two clinical trials. The test reaches patients and generates new questions that you have to answer biologically,” he summarizes.
The research has received support from Fundació “la Caixa” through the 2018 call for health research. It has also received funding from the Spanish Association Against Cancer, the FERO Foundation, the BBVA Foundation and the Spanish Ministry of Science. and Innovation. In addition, the study has had the patronage of Mrs. Carme Segura Capellades, who contributes to cancer research at IRB Barcelona.
