Harmful variant of breast cancer sparks urgent search for a cure

Breast cancer is the most common among women and, in Europe alone, causes almost 92,000 deaths a year.

Although this number is undoubtedly high, the survival rates are increasing.

Advances in prevention, detection and treatment have made it possible for today's survival rate to be 90%.

However, a particularly aggressive variant, triple-negative breast cancer (TNBC), so named because it lacks three types of cellular proteins, behaves differently.

Tumors of this type account for about 15% of breast cancer cases, and the prospects for recovery are much worse than for other types.

Tumors grow faster, often spread before being detected, and the risk of recurrence after treatment is greater.

And if the CMTN spreads to other organs, the risk of premature death is high, since the survival rate is only 11%.

Currently there is no specific treatment for this type of breast cancer.

Most commonly, it is treated with surgery to remove the tumor, followed by the use of a cocktail of chemotherapy drugs known to be effective against other types of cancer.

However, the results are often patchy and temporary.

“After a while, the body builds defenses against this cocktail and the treatment stops working,” says Andreia Valente, coordinator of an EU-funded project to find a cure for CMTN.

"When this happens, the tumor becomes resistant to many drugs, which means it doesn't respond to any other type of chemotherapy, and the cancer then becomes very aggressive."

Valente, who works at the University of Lisbon, Portugal, and her research partner, Helena Garcia, coordinate CancelRusolution, a year-long Women TechEU initiative that will run until the end of May 2023.

a rare metal

The efforts of these researchers are focused on ruthenium, a rare, silvery-white metal that is well tolerated by the human body.

In the first trials, everything seems to indicate that the ruthenium-based drug developed by the project team stops the growth of CMTN cells and their proliferation.

A second series of tests is scheduled to begin shortly, this time on animals.

Apart from the trials, the researchers will look at the drug's safety profile to make sure it is toxic to cancer cells but harmless to the rest of the body.

And is that chemotherapy causes devastating side effects, from nausea and lack of appetite to extreme fatigue and hair loss.

This is due to the fact that drugs that attack the rapidly growing cells of a tumor also attack healthy cells.

Early results from CancelRusolution suggest that a ruthenium-based drug would produce fewer side effects in patients because it appears to spare healthy cells.

"For now, in terms of toxicity, the profile of the drug is good," says Garcia.

“Our studies show that, 24 hours after having administered the drug, there is a high concentration of the compound in the tumor, but its presence in the blood close to the tumor and in the urine is almost non-existent.

This indicates that our drug will produce mild side effects,” he adds.

Cell characteristics

A healthy mammary cell contains a multitude of receptors (proteins), which are expressed on its surface.

These proteins allow the cell to respond to hormones (for example, increasing in size during pregnancy) and other important molecules involved in cell growth, division, and repair.

Most cancer cells also have receptors.

Therefore, to make an accurate diagnosis, a sample of the affected breast tissue is analyzed in order to discover which receptors, known as biomarkers in this context, are expressed.

More information

Survival against aggressive tumors is already counted for years

There are three biomarkers that are commonly found in breast cancers and the drugs developed are designed to address them.

However, the CMTN is an outlier.

It does not have any of these biomarkers, so there is no clear way to stop tumor growth.

Trojan horse strategy

The Portuguese team has circumvented this problem by administering their drug in the form of nanoparticles, which are introduced into the tumor, taking advantage of any deficiency in its blood supply system.

Once inside, it opens and releases the active ingredient, emulating the Trojan horse.

The drug's target is a different component of CMTN cells: the cytoskeleton, a complex network of interconnected protein filaments that stretch throughout the interior of the cell and serve as scaffolding.

"The drug destroys the foundations of the cell," Garcia says.

“Without a proper cytoskeleton, the cell has no chance of surviving and it explodes,” he adds.

With more funding, the researchers expect their drug to be ready for human trials within two years.

a diverse group

Considering CMTN as a single type of cancer would be an oversimplification.

In reality, this is a very heterogeneous group of cancers.

However, the research community does not have a classification of the subtypes.

Obtaining one would allow them to focus all their attention on new biomarkers, which are expected to pave the way for the development of targeted treatments.

Classifying patients by the characteristics of their tumor and establishing new objectives for the treatment of CMTN are the pillars of another project financed by the EU: P70-IMMUNEBREAST.

After studying 350 samples of cancerous tissue, the project's research team has devised a classification system based on the amount of kinase, an enzyme and other cancer biomarker, expressed in the tumor.

Previous research has shown that a certain type of kinase, P70S6K, is present at high levels in CMTN tumors.

"What interests us is the relationship between this kinase and the body's immune response," says Rebeca Jimeno, researcher.

“Tumors can develop in our body, but if all goes well, our immune system recognizes it and destroys it,” she adds.

The big question is why this system sometimes fails.

the immune system

Jimeno, who works for the Spanish National Cancer Research Center (CNIO), has found that when high levels of P70S6K kinase are expressed in a tumor, few B cells are present.

B cells are responsible for recognizing, deceiving and destroying cancer cells.

In other words, P70S6K allows cancer to hide from the immune system and thrive unhindered.

One of the next steps in this research is to find a suitable inhibitor of this kinase.

“We are testing drugs, but I suspect it will be several years before we find one that is well tolerated by the body,” he reveals.

Jimeno is confident that in time a cure will be found.

“We're trying so hard to find a solution and fill this unmet need that I'm sure research will eventually do it,” she concludes.

The research referred to in this article has been funded through the Marie Skłodowska-Curie Actions (MSCA).

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