A research team from Barcelona has identified a key enzyme in the origin of metastases in some types of breast cancer, which opens the door to developing drugs that help prevent metastases. The finding, which was published yesterday in the journal Nature Cell Biology, was the result of uncovering the mechanisms by which some patients are more prone than others to suffer the spread of cancer cells to other parts of the body.
The work focuses on women who have breast cancer and tumor cells with high levels of a protein called MAF. These patients, approximately one in five affected by breast tumors, have a greater risk of metastasis, and do not benefit from the preventive treatments that are usually administered to prevent cancer cells from implanting in the bones, called bisphosphonates . On the contrary, in many cases, especially among young patients, the prognosis worsens after treatment with bisphosphonates.
"This discovery represents a critical step in understanding how breast cancer spreads, and opens up new therapeutic opportunities for the 20% of patients who cannot benefit from bisphosphonate treatment," explains Roger Gomis, the researcher at the 'Institute of Biomedical Research of Barcelona (IRB) which led the study.
Scientists have observed, in tests in cell cultures and with mice, that if they block a single enzyme of all the molecules involved in the metastatic process, called KDM1A, the cancer cells see a reduced ability to jump to other organs. To block the enzyme, the IRB team used an inhibitor independently found by other research groups.
The study, in which the Center for Genomic Regulation (CRG), 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 metastases in a group of breast cancer patients particularly susceptible to this complication. In fact, the inhibitor they used is being administered in a phase two clinical trial for the treatment of acute myeloid leukemia, a class of blood cancer.
If it confirms the safety and effectiveness of the treatment, points out Gomis in a conversation with La Vanguardia, it may be a good candidate for preventive treatment of patients who have high levels of MAF.
Despite everything, the researcher is cautious about a hypothetical clinical application of the treatment, since it takes years to transfer the results of laboratory research to the treatment of patients.
The group led by Gomis discovered the relationship between high MAF levels, higher risk of metastasis and poor performance of bisphosphonate treatment seven years ago. The results led the scientist to found the company Inbiomotion, with which he developed a test to detect which patients have high MAF levels. The aim was to "give information to oncologists about which patients can be treated with bisphosphonates to prevent metastases and which cannot", explains the expert.
Bisphosphonates prevent cancer cells from implanting in the bones, the most common metastatic process in breast cancer. The problem is that in some cases they can divert metastases to other organs, such as the liver or brain, so that much worse complications can arise. This risk is greater among patients with high MAF levels, 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. However, the mechanism underlying these associations has remained a mystery to this day.
Now, researchers have deciphered 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 the estrogen receptor, well-known in the oncology field because it is responsible for the growth of cancer in 70% of breast tumors. This interaction restructures the DNA of cancer cells and turns them into "metastasis machines", Gomis describes.
After 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 patients having a greater risk of developing metastasis. Without the enzyme, the researchers think, the likelihood 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 came from a discovery seven years ago, which led us to develop a test, which was validated in two clinical trials. The test reaches the patients and creates new questions, which you have to answer biologically", he summarizes.
The research has received the support of the La Caixa Foundation through the call for research in health 2018. It has also received funding from the Spanish Association Against Cancer, the FERO Foundation, the BBVA Foundation and the Ministry of Science. In addition, the study has the patronage of Carme Segura Capellades, who contributes to cancer research at IRB Barcelona.
