According to the Washington University School of Medicine in St. Louis, the University of the Alpes in Grenoble, France, and the University of Texas MD Anderson Cancer Center in Houston.
One of the drugs, cyclophosphamide, is an outdated chemotherapy drug once used to treat small cell lung cancer. It was replaced by platinum drugs in the 1980s. Both drugs were effective at first, but faltered after a few months as the cancer developed resistance. Platinum-based drugs have become the standard of care primarily because they cause fewer side effects, but they have not significantly improved outcomes. Today, the typical patient lives less than a year and a half after diagnosis.
In this study, however, the researchers showed that small-cell lung cancer cells resist cyclophosphamide by activating a specific repair process, and demonstrated that throwing a wrench into the repair process makes the drug more effective, at least in mice. The findings, available online at Cancer Discovery, lead to better treatments for one of the most difficult forms of cancer to treat.
“There is one treatment option for small cell lung cancer — platinum-based chemotherapy — that may add two to six months of life,” said co-senior author Nima Mosammaparast, associate professor of pathology and immunology. University of Washington, MD, research fellow at Barnes-Jewish Hospital Sterman Cancer Center and Washington University School of Medicine. “The problem is that these tumors initially respond to treatment, but then they come back. That hasn’t changed in 30 years. These tumors are very resistant to almost everything. So this study shows that we can actually Incorporating a new drug that targets an older drug to reduce resistance and potentially make treatments better and provide better opportunities for these patients.”
The research came together by chance. Co-senior author Nicolas Reynoird, Ph.D., professor at the University of the Alpes in Grenoble, studies internal signaling within cells — and how dysregulation of this signaling — contributes to cancer progression and drug resistance. A few years ago, his team discovered that a protein called RNF113A may play a role in small-cell lung cancer, but researchers were unable to pinpoint the protein’s role. Meanwhile, Mosammaparast is studying how cells repair damaged DNA. In 2017, he published a paper in the journal Nature describing how cancer cells repair a type of DNA damage called alkylation damage, which is caused by cyclophosphamide. The paper notes that RNF113A plays a role in this process. Reynoird, basically coldly known as Mosammaparast, and the two collaborated with co-senior author Pawel K. Mazur, Ph.D., associate professor of experimental radiation oncology at MD Anderson and longtime Reynoid collaborator, to study how small-cell lung cancer cells resist alkylation damage, and whether it’s possible The effects of alkylating chemotherapeutics such as cyclophosphamide are amplified by interfering with this resistance.
The team found that RNF113A is regulated by a protein called SMYD3, which is highly expressed in small cell lung cancer and some other cancers. High levels of SMYD3 are associated with more aggressive disease, increased resistance to alkylating chemotherapy, and poorer prognosis. There is very little SMYD3 in healthy lung tissue, leading the researchers to think that knocking it down might target cancer cells while sparing healthy cells.
So they tried it. The researchers created mouse models of the human disease by transplanting cancer cells from two people with small-cell lung cancer onto separate groups of mice. One group of cells came from patients who had not yet received treatment, so the cells had no chance of developing resistance. The other was from a patient who had received standard platinum therapy and developed resistance to it.
All mice developed tumors. When the tumors were large enough, the researchers treated the mice with an SMYD3 inhibitor, cyclophosphamide, or both, or an inactive solution. Inhibition of SMYD3 alone moderately slowed tumor growth. Cyclophosphamide initially stopped tumor growth in both patients, but the tumors started growing again about two weeks later, suggesting they had developed drug resistance. However, the combination of the two drugs stopped the tumor from developing. During the experiment, they did not start growing again.
“We are in discussions with some other groups to start a Phase 1 clinical trial as soon as possible,” Mosammaparast said. “One of the challenges we’re going to face is convincing physicians to revert to old drugs. But the benefit of this strategy is that it may work where current therapies fail. This therapy works just as well in patients with tumors that are already in platinum-based therapy. relapse in patients, as it is for untreated patients. People with small cell lung cancer desperately need better treatments, and I’m very excited about the possibilities here.”