CNIO Transformation and Metastasis Group. Marina Ciscar, the first author of the paper, standing first from the right. The group is led by Eva González-Suarez, seated in the center; after her, the co-author Maria Jiménez. Gema Pérez, first from the left (below), is also a co-author. / Laura M. Lombardía. CNIO
A therapeutic study of this drug in postmenopausal patients with breast tumors and hormone-negative Ranke protein expression.
“These results reactivate the option of opening clinical trials with denosumab in select breast cancer patients,” says Eva González-Suarez, CNIO researcher and lead author.
The results are published today in the scientific journal “Embo Molecular Medicine”.
The drug denosumab is currently used to treat bone metastases and osteoporosis. For more than a decade, its potential medicinal benefit in the treatment of breast cancer has also been investigated. However, given the conflicting clinical data, the survival benefit for breast cancer patients is uncertain.
In order to find patients who could benefit from this drug, researchers from the National Cancer Research Center (CNIO) and Biomedical Research Bellvitge (IDIBELL), led by Eva González-Suárez, analyzed the expression of the GRADUS protein and its RANKL ligand in more than 2,000 breast tumors, 777 of them without hormone receptor expression, from four independent cohorts.
Their results show that Rank protein expression is more frequent in tumors without hormone receptors, where it is associated with poor prognosis and poor response to chemotherapy. In addition, the researchers observed greater activation of the ORGAN pathway in breast tumors after menopause, thus, the use of the inhibitor denosumab, added to the basic treatment, could have a greater therapeutic effect in postmenopausal patients with breast tumors. the chest and the address of the protein were said.
Hormone receptor-negative tumors, in which the cancer cells do not contain receptors for estrogen and progesterone, have a poorer prognosis and limited treatment options. “Given the heterogeneity of the group having hormone-negative breast tumors, biomarkers that better distinguish the prognosis of these patients is essential, especially if these markers enable the most appropriate treatment to be selected,” says Eva González-Suárez, head of the CNIO Transformation and Metastasis team.
“The confidence of the event is great,” adds this researcher. “Subject patients are a group that could benefit from denosumab treatment, and the option of opening chest trials is exciting by selecting patients.”
The next step would therefore be to “design a clinical trial in patients with hormone-negative tumors that express the receptor sequence both in pre- and postmenopause.”
RANGE in different breast tumors
The protein Rank is located in the cell membrane and, when it binds to RANKL, it sends key signals that allow proper mammary development and milk production. In previous studies, González-Suárez and other authors showed that inhibiting RANKL with inhibitor drugs, such as denosumab, could be a way to prevent the disease.
Subsequently, González-Suárez and his team demonstrated that pharmacological inhibition of the RANKL/RANKL pathway reduced recurrences and metastases in mouse models of breast cancer. The following steps focused on a further understanding of this relationship between GRADE and various human breast tumors, the great heterogeneity that the disease shows in patients.
The GRADE protein was initially described for its role in immunity. Later it was discovered that it has a key role in bone metabolism: the activation of the LINE pathway is necessary for the differentiation and function of osteoclasts, the cells responsible for bone resorption, hence the first indication of denosumab in osteoporosis and bone metastases. “This is a well-known and therapeutically abused function of nobility,” explains González-Suárez. “Later, in our group we showed that it is also relevant in the development of the breast: we noticed that progesterone acts as a mediator, essential for its ability to produce milk, but also in the formation of breast cancer. Let’s say that for a tumor, breast epithelial cells must divide, but if you block the pathway that is the main mediator of that division, you can prevent breast cancer.”
Over 2,000 samples from four bands
In this new study, Marina Ciscar and Eva M. Trinidad, co-authors of the first study, are trying to determine the therapeutic value of the ORN pathway in breast cancer. Ciscar and other members of the González-Suárez team followed these films from more than 2,000 breast tumors from four old cohorts, mainly from Emad Rakha’s team at the University of Nottingham, where they followed patients from two decades ago, and two Spaniards, from the Bellvitge Institute Biomedici (Idibell) and CNIO.
Ciscar et al. 40% of hormone-negative tumors expressed the Ranke receptor, and this expression was associated with poorer prognosis and patient survival.
For that part, Eva M. Trinidad used experimental mice as examples, in which she transplanted a small piece of human tumors into the same organ of origin. In these models, RANKL inhibition reduced human tumor cell proliferation and plasticity, regulated tumor immunity and metabolism, and improved response to chemotherapy. In this way, the researchers concluded that the RANGE pathway could serve as a biomarker and even a therapeutic target.
“This work began in 2014, thanks to the support of the American Susan Komen Breast Cancer Foundation, and during these years it was supported by other sources of funding, including the national and European Research Council (ERC), and thanks to researchers from Idibell, Cnio and Nottingham among others.
This research draws from previous observations, where we already saw that the receptor is more frequently expressed in tumors without hormone receptors. In the present work, the analysis is much more powerful and allowed us to conclude that, within tumors not having hormone receptors, or not having the receptor sequence, is associated with the prognosis of the disease”, explains González-Suárez.
Two large phase III clinical trials, with the primary goal of preventing bone metastases in breast cancer, also tested whether denosumab had an effect on overall survival in women. The results were contradictory, but the truth is “no test analyzed the expression of the receptor in patients: they did not see whether the tumor expresses the receptor or not, which is a fundamental point. When the results of one of the studies were negative, the door was somewhat closed to make tests in breast cancer with denosumab .I believe that this work will reactivate the ability to do it again by choosing patients”, concludes the researcher.
Ciscar M, Trinidad EM, Perez-Chacon G, Alsaleem M, Jimenez M, Jimenez-Santos MJ, Perez-Montoyo H, Sanz-Moreno A, Vethencourt A, Toss M, Petit A, Soler Monso MT, Lopez V, Gomez. -Miragaya J, Gomez-Aleza C, Dobrolecki LE, Louis MT, Bruna A, Mouron S, Quintela-Fandino M, Al-Shahrour F, Martinez-Aranda A, Sierra A, Green AR, Rakha E, and Gonzalez-Suarez E (2023) GRADE is a poor prognosis and therapeutic target in ER-negative postmenopausal breast cancer. EMBO Mol Med
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