Experimental drug treatment stops deadly form of lung cancer in mice: ScienceAlert

Using an experimental combination of two drugs, scientists were able to effectively halt the progression of small cell lung cancer – a deadly form of lung cancer – in tests on mice. Now, following these promising results, human trials are planned.

One of the drugs cyclophosphamidehas been used relatively little to treat small cell lung cancer since the 1980s, when it was replaced by alternatives that had fewer side effects.

However, whether cyclophosphamide or the alternatives are used, the cancer quickly develops resistance to treatment.

Now the team behind the new experiments has been able to identify how small cell lung cancer cells resist the effects of cyclophosphamide – and do something about it.

The technique they developed essentially blocks the repair process that cancer cells use to develop resistance to cyclophosphamide.

“The problem is that these tumors initially respond to treatment, but then they come back. That hasn’t changed in 30 years,” he added. says pathologist and immunologist Nima Mosammaparast from Washington University in St. Louis.

“These tumors are just massively resistant to just about anything.”

The new findings are based on Previous search from the same team that identified the RNF113A protein as being involved in the repair of cancer cells – specifically, in the repair of a type of DNA damage known as alkylation damage, the type caused by cyclophosphamide.

Further research revealed that RNF113A is regulated by SMYD3, a protein highly expressed in small cell lung cancer and present at higher levels in more invasive forms of the disease. High levels are also associated with increased resistance to alkylating chemotherapeutic agents (the category that includes cyclophosphamide) and poorer overall prognosis.

In contrast, healthy lung tissue has very low levels of SMYD3.

Armed with this knowledge, the researchers attempted to target SMYD3 in mice in which the team had transplanted human lung tumors – some of which had already been treated with chemotherapy and some which had not.

While cyclophosphamide temporarily worked alone and an SMYD3 inhibitor slowed tumor growth to some extent, it wasn’t until the two treatments were combined that the cancer stopped growing altogether.

This tumor suppression lasted for the duration of the experiment (approximately one month), long after other single treatments had failed.

“What this study shows is that we can actually combine a new target with an old drug to reduce resistance and potentially improve treatment and give these patients a much better chance,” said Mosammaparast.

It’s still early days – not least because it’s only been tested in mice – and scientists want to experiment more to see if they can reduce the level of cyclophosphamide involved to limit the toxic side effects that led to the cessation of its original use.

What is clear, however, is that the drugs that replaced cyclophosphamide are no better at fighting small cell lung cancer, even though they are less harmful to the body. Current treatment options can only add about two to six months to life.

Now, the researchers plan to organize phase 1 clinical trials in humans. One of the promising aspects of the research is that it shows signs that it might work on cancers that have already become resistant to certain treatments.

“One of the challenges we will face is convincing doctors to go back to an old drug,” said Mosammaparast. “But the good thing about this strategy is that it can work where current therapies have failed.”

The research has been published in Discovery of cancer.

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