Study in mice revealed that combination therapy stops the progression of lung cancer

An experimental combination of two drugs stops the progression of small cell lung cancerthe deadliest form of lung cancer, according to a study in mice by researchers at Washington University School of Medicine in St. Louis, the University of Texas MD Anderson Cancer Center in Houston, and the Grenoble Alpes University of Grenoble (France).

One of the drugs, cyclophosphamide, is an outdated chemotherapy drug that was used to treat small cell lung cancer. It was displaced in favor of platinum-based drugs in the 1980s. Both types of drugs work at first, but fail after a few months when the cancer develops resistance.

In this study, the researchers have shown that small cell lung cancer cells resist cyclophosphamide by activating a specific repair process, showing that throwing a lever in the repair process makes the drug much more effective. effective, at least in mice.

“Small cell lung cancer has only one treatment option (platinum chemotherapy) and that gives you between two and six months to live”says study co-author Dr. Nima Mosammaparast, an associate professor of pathology and immunology and of medicine at the University of Washington.

How does the study was realized?

The study was conducted randomly. Dr. Nicolas Reynoird, co-author of the study and professor at the University of Grenoble Alpes, studies how internal cell signaling and its deregulation can lead to cancer progression and drug resistance.

A few years ago, his team discovered that a protein called RNF113A might play a role in small cell lung cancer, but the researchers couldn’t figure out what the protein does.

Meanwhile, Mosammaparast was studying how cells repair damaged DNA. In 2017, she published an article in the magazine Nature, in which he described how cancer cells repair a type of DNA damage known as alkylation damage, the kind caused by cyclophosphamide.

Reynoird called Mosammaparast, and the two teamed up to investigate how small cell lung cancer cells resist alkylation damage, and whether it’s possible to magnify the effects of alkylating chemotherapy drugs, such as cyclophosphamide, by interfering with that resistance.

The team found that RNF113A is regulated by a protein called SMYD3 that is highly expressed in small cell lung cancer and some other types of cancer. Elevated levels of SMYD3 are associated with more invasive disease, greater resistance to alkylating agent chemotherapy, and poorer prognosis.

Healthy lung tissue has very little SMYD3, which led the researchers to think that removing it could attack cancer cells while sparing healthy ones.

The researchers created mouse models of the human disease by grafting cancer cells from two people with small cell lung cancer into separate groups of mice.

One group of cells came from a patient who had not yet been treated, so the cells had not had a chance to develop resistance. The other came from a patient who had been treated and had become resistant to standard platinum-based therapy.

All the mice grew tumors. When the tumors were large enough, the researchers treated the mice with an SMYD3 inhibitor, cyclophosphamide, both, or an inactive solution.

SMYD3 inhibition alone modestly slowed tumor growth. Cyclophosphamide initially stopped the growth of the tumors in both patients, but they grew again after about two weeks, indicating that they had developed resistance. However, the combination of the two drugs stopped the tumors in their tracks. They did not grow back during the experimentwhich means that the test worked in mice.

*With information from Europa Press.

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