A study in mice revealed that the combination therapy halted the progression of lung cancer

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

One of the drugs, cyclophosphamide, is an outdated chemotherapy drug used to treat small cell lung cancer. It was superseded in favor of platinum-based drugs in 1980.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

In this study, 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, 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 Nima Mosamaparast, MD, associate professor of pathology and immunology and medicine at the University of Washington.

How was the survey implemented?

The study was conducted on a random basis. Dr. Nicolas Reynoird, co-author of the study and professor at the University of Grenoble Alpes, studies how intrinsic 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 researchers couldn’t figure out what the protein did.

Meanwhile, Mosammaparast studied how cells repair damaged DNA. In 2017, he published an article in nature, in which he describes how cancer cells repair a type of DNA damage known as cyclophosphamide-induced alkylation damage.

Reynoird called Mosammaparast, and the two teamed up to study how small cell lung cancer cells resist alkylation damage and whether it might be possible to increase the effects of alkylating chemotherapy drugs, such as cyclophosphamide, by interfering with this resistance.

The team found that RNF113A is regulated by a protein called SMYD3, which is highly expressed in small cell lung cancer and some other cancers. Increased levels of SMYD3 are associated with more invasive disease, greater resistance to chemotherapy with alkylating agents, 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 transplanting 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 became resistant to standard platinum-based therapy.

All mice developed 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 slows 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. They did not grow back during the experimentmeaning the test worked in mice.

*With information from Europa Press.

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