Experimental Drug Combination Halts Lung Cancer in Mice

By Emily Menendez - Last Updated: December 19, 2022

A new experimental drug combination has been found to stop the growth of small cell lung cancer (SCLC) in tests on mice. SCLC is known as the deadliest form of lung cancer and often becomes resistant to chemotherapy, leaving no alternative treatment options for patients. The two drugs—cyclophosphamide and an SMYD3 inhibitor—both work individually to slow down tumor growth when used on their own, but they tend to stop working after several months when the cancer begins building resistance. However, pairing the two together resulted in a complete stop of cancer growth. 

SMYD3 inhibition has been found to sensitize cells to alkylating agents and can promote sustained SCLC response to chemotherapy, and cyclophosphamide is an alkylating agent that can work in tandem with SMYD3 to damage SCLC cells with alkylation. 

The History of Cyclophosphamide and SMYD3 

The combination of cyclophosphamide and SMYD3 was discovered in a study carried out by Lukinović V, Hausmann S, Roth GS, et al. Cyclophosphamide is considered an outdated drug that was replaced in favor of platinum-based drugs for the treatment of SCLC in the 1980s. Platinum-based drugs cause less side effects, but this treatment has not improved survival rates; the average patient typically survives less than a year and a half after diagnosis. 

The research team had previously discovered that a certain protein called RNF113A plays a role in SCLC, and that it is regulated by the SMYD3 protein which is highly expressed in SCLC. Higher levels of SMYD3 are associated with more invasive disease, a stronger resistance to alkylating chemotherapy, and worse prognosis for patients. Normally, healthy lung tissue carries a very small amount of SMYD3, and the research team hypothesized that knocking it down may target cancer cells while sparing healthy cells. 

SCLC Treatment Trials Begins 

The research team used cancerous cells from two SCLC patients to create mouse models of the disease in separate groups of mice. One group has cells that had not yet been exposed to any treatment, and the other group’s cells came from a patient who had previously been treated with (and became resistant to) platinum-based chemotherapy. Once tumors had developed, the mice were treated with either a SMYD3 inhibitor, cyclophosphamide, or both. Cyclophosphamide and SMYD3 alone both slowed down the growth of the tumors initially, but the tumors grew resistance and began growing again after two weeks. 

The combination of cyclophosphamide and SMYD3 halted the growth of the tumors and also stopped them from restarting their growth for the rest of the duration of the experiment. The research group is currently looking to start phase 1 clinical trials of the drug combinations in humans. Co-senior author of the study, Nima Mosammaparast, MD, PhD, said that their main challenge will be convincing doctors to go back to using an old drug. “But the nice thing about this strategy,” Mosammaparast added, “is that it may work where current therapies have failed. This treatment worked just as well against the tumor from the patient who had already relapsed on platinum-based therapy as it did against the untreated patient. People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.” 


SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage Through RNF113A Methylation–Phosphorylation Cross-Talk 

Experimental Drug Treatment Stops a Deadly Form of Lung Cancer in Mice