Small cell lung cancer (SCLC) is one of the deadliest forms of the disease, but now scientists may have a promising new avenue for treatment. By combining a new drug with an outdated one, the team found that they could halt growth of tumors in mice.
Most commonly occurring in smokers, small cell lung cancer is an aggressive form of the disease with a low survival rate. While chemotherapy is effective initially, the cancer can quickly develop a resistance to the drugs, leading to recurrence and progression of the disease.
For the new study, researchers at Washington University in St. Louis, Grenoble Alpes University and the University of Texas investigated how SCLC cells resist the damage caused by chemotherapy, and how that could be countered.
In previous work, the scientists found that a protein called RNF113A was implicated in cancer cells’ ability to repair alkylation damage, which is the mode of attack for common chemotherapy drugs. On closer inspection, the team discovered that RNF113A is regulated by another protein, SMYD3, which is expressed in higher amounts in SCLC cells and other cancers. In particular, higher levels of SMYD3 are linked to more aggressive cancer and stronger drug resistance.
With this new target in their sights, the scientists examined whether blocking SMYD3 could improve the effects of chemotherapy drugs. The team grafted human SCLC cells into mice, and waited until they grew tumors in their lungs. Then, they treated some mice with a drug called cyclophosphamide, some with an SMYD3 inhibitor, some with both, and some with none.
In mice given the chemotherapy alone, the tumors stopped growing for about two weeks before starting up again, indicating drug resistance had built up. But in the mice given both cyclophosphamide and the SMYD3 inhibitor, the tumors stopped growing for the entire several-month duration of the experiment. Intriguingly, the treatment worked just as well on tumors grown from a human patient whose cancer had already developed resistance to chemotherapy drugs.
Cyclophosphamide has somewhat fallen out of favor in recent decades, thanks to its stronger side effects compared to platinum-based chemotherapy agents, but the new study might mean it's worth dusting off. The team hopes that the research could lead to new treatments for an aggressive form of cancer for which there are currently few options.
“We’re talking to a number of other groups about starting a phase 1 clinical trial as soon as possible,” said Nima Mosammaparast, co-senior author of the study. “People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.”
The research was published in the journal Cancer Discovery.