Combination therapy halts lung cancer tumour growth in mice

Small cell lung cancer

An experimental combination of two drugs halts the progression of small cell lung cancer, the deadliest form of lung cancer, according to a recent study.

The discovery was made by researchers at Washington University School of Medicine in St Louis, Grenoble Alpes University in Grenoble in France, and The University of Texas MD Anderson Cancer Center in Houston.

It signals the first potential breakthrough in this difficult-to-treat cancer for 30 years.

One of the drugs, cyclophosphamide, was once used to treat small cell lung cancer, but was displaced in favour of platinum-based drugs in the 1980s.

Although both kinds of drugs falter after a few months as the cancer develops resistance, platinum-based drugs became the standard of care because they cause less side effects.

A pathway to better therapies

Today, the typical patient survives less than a year and a half after diagnosis. In this study however, researchers showed that small cell lung cancer cells resist cyclophosphamide by activating a specific repair process. Hindering this repair process makes the drug much more effective. 

The findings suggest a pathway to better therapies for one of the least treatable forms of cancer.

Small cell lung cancer
Tumours (yellow) pervade the lungs of mice genetically prone to small cell lung cancer (left) on this computed tomography scan. Researchers have found that a chemotherapy drug plus blocking resistance makes the tumours virtually disappear (right). Credit: Simone Hausmann and Pawel Mazur.

“Small cell lung cancer has one treatment option — platinum-based chemotherapy — and that adds maybe two to six months of life,” said co-senior author Nima Mosammaparast, MD, PhD, Associate Professor of Pathology & Immunology and of Medicine at Washington University, and a researcher at Siteman Cancer Centerat Barnes-Jewish Hospital and Washington University School of Medicine. 

“The problem is that these tumours respond to treatment initially, but then they come back. This has not changed for 30 years. What this study shows is that we can actually combine a new target with an old drug to reduce resistance and potentially make the treatment much better.”

Phase I trial on the horizon

Several years ago, co-senior author Nicolas Reynoird, PhD, a Professor at Grenoble Alpes University, and his team discovered that a protein called RNF113A may play a role in small cell lung cancer but could not determine what the protein does.

Mosammaparast published a paper in the journal Nature in 2017 describing how cancer cells repair a kind of DNA damage known as alkylation damage, the kind caused by cyclophosphamide, noting that RNF113A plays a role in the process.

Reynoird contacted Mosammaparast and the two teamed up, along with co-senior author Pawel K Mazur, PhD, Associate Professor of Experimental Radiation Oncology at MD Anderson.

The team discovered that RNF113A is regulated by a protein called SMYD3 that is highly expressed in small cell lung cancer and some other cancers. High levels of SMYD3 are associated with more invasive disease, increased resistance to alkylating chemotherapy and worse prognosis.

In the study, combining the SMYD3 inhibitor with cyclophosphamide stopped the tumours growing completely.

“We’re talking to a number of other groups about starting a Phase I clinical trial as soon as possible,” Mosammaparast said. “One of the challenges we will face is convincing doctors to go back to an old drug. But the nice thing about this strategy is that it may work where current therapies have failed. People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.”

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