An already approved drug could contribute to eliminating resistance to the most effective treatment against metastatic breast cancer.
Breast cancer is the most common in women. Among breast tumors that spread to other organs (metastasize) 70% are of the luminal type, a variant in which the cells are sensitive to the female sex hormones, estrogen and progesterone. In fact, the tumor forms when these hormones tell the cells to divide. In advanced cases, the usual treatment is surgery, followed by hormonal therapy alone or in combination with chemotherapy or targeted therapy.
Targeted therapies attack specific molecules in the tumor. In luminal breast cancer, targeted therapy consists of drugs that annul –inhibit– the CDK4/6 proteins, responsible for the speed of cell growth and division. The approval of these inhibitors represented an important advance in the treatment of luminal breast cancer.
However, about 20% of patients do not respond to treatment. And most of those who do respond develop resistance in the first two years, meaning the therapy loses effectiveness.
A team made up of, among others, Inês Gomes, Luís Costa and Sandra Casimiro, from the João Lobo Antunes Institute of Molecular Medicine (IMM) in Portugal, as well as Eva González Suárez and Maria Jiménez, from the National Cancer Research Center (CNIO) in Spain, have discovered one of the mechanisms that cause this resistance, and propose a way to combat it.
Eva González Suárez, head of the Transformation and Metastasis Group at the CNIO. (Photo: Laura Lombardía / CNIO. CC BY)
The research focuses on the RANK protein, which is known to be involved in the renewal process of cells in our bones. “Our work and that of other authors had already shown that RANK also has a role in breast cancer, both in the initiation and in the progression of the tumor,” says González Suárez, head of the Transformation and Metastasis Group.
In this new work, the IMM and CNIO researchers have verified that excess RANK in tumor cells fosters resistance to CDK4/6 inhibitors. And that also weakens a tool of the immune system against tumors, gamma interferon. In other words, patients with too much RANK protein are left without their body’s natural defense and also do not respond to the most common and effective treatment.
These results have clinical value. On the one hand, a patient’s RANK levels could help decide whether to give her CDK4/6 inhibitors. On the other hand, further research could be carried out to complement the combined hormonal and targeted therapy with a third drug that blocks the action of RANK and eliminates resistance.
The study proposes the drug denosumab, a monoclonal antibody approved in the United States and Europe to treat osteoporosis, prevent bone metastases, and skeletal damage from other types of cancer.
“The advantage is that, since it is already approved, we know a lot about its safety profile. The side effects it may have are already known and, in the context of cancer, are minor. For this reason, from the research point of view, a clinical trial with patients could be immediately designed”, says González Suárez.
That would be the next step, in order to apply the results obtained. “It is the obvious step, for the publication we have only worked with cell lines and mouse models without an immune system, a very important piece of information. The clinical trial in patients is what would confirm if there really is a benefit of the combination of denosumab with the combined therapy of hormones and CDK4/6 inhibitors”, explains González Suárez.
The study is titled “Approved drug could help overcome resistance to primary treatment against metastatic breast cancer”. And it has been published in the academic journal Cell Reports Medicine. (Source: CNIO)
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