Human trials are now being planned after an experimental combination of two drugs has seen success in halting the progress of small cell lung cancer in mice.

Cyclophosphamide, one of the drugs, has been relatively inactive in the treatment of small cell lung cancer since the 1980s, when it was replaced by alternatives with fewer adverse effects.

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

"The problem is that these tumors respond to treatment initially, but then they come back. This has not changed for 30 years," pathologist and immunologist Nima Mosammaparast from Washington University in St Louis, said.

"These tumors are just massively resistant to just about everything."

The team behind the new experiments has now been able to pinpoint the mechanism by which small cell lung cancer cells resist cyclophosphamide's effects and develop a remedy for it.

The approach they've devised essentially prevents the cancer cells' ability to mend themselves and develop cyclophosphamide resistance.

The new research expands on earlier work from the same group that showed the protein RNF113A was crucial for cancer cell repair, specifically for the repair of DNA damage known as alkylation damage, which is the kind brought on by cyclophosphamide.

Further investigation demonstrated that RNF113A is regulated by SMYD3, a protein present in higher amounts in more aggressive forms of small cell lung cancer. Elevated levels are also linked to increased susceptibility to alkylating chemotherapeutic medicines (including cyclophosphamide) and a poor prognosis.

In contrast, SMYD3 levels in healthy lung tissue are extremely low.

Using this information, the researchers attempted to target SMYD3 in mice into whom they had implanted human lung cancers, some of which had previously been treated with chemotherapy and others that had not.

While an SMYD3 inhibitor and cyclophosphamide both temporarily reduced tumor development, it was only when the two treatments were combined that the disease entirely ceased spreading.

Long after other one-off therapies had failed, this tumor suppression persisted for the remainder of the experiment (approximately one month).

"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 and give these patients a much better chance," Mosammaparast said.

The researchers are now working to start phase 1 clinical trials in humans. One of the promising elements of the research is that it shows evidence of being able to work on tumors that have already developed resistance to some treatments.

The research has been published in Cancer Discovery.