Drugs That Control Genes May Treat Lung Cancer

 

Researchers Report Some Success Against Advanced Lung Cancer With Epigenetic Drugs

A new approach to treating cancer appears to help certain patients with advanced lung cancer, and researchers say they think they may have a way of spotting those who will benefit.
The small study is generating big excitement in the world of cancer treatment because it demonstrates that so-called epigenetic drugs may work when traditional chemotherapy has failed.
Epigenetic drugs work by controlling gene expression -- the way information from genes is used to create products such as proteins.
The study is published in Cancer Discovery.
"This is a ... groundbreaking study, showing that by modifying the epigenetics of a cancer cell we can get real responses in lung cancer," said Jeffrey A. Engleman, MD, PhD, director of thoracic oncology at Massachusetts General Hospital, in Boston, in a news briefing. "And getting real responses in lung cancer is actually quite difficult, so we take special notice of therapies that can do this." He was not involved in the research.

New Approach to Treating Cancer

All 45 patients recruited for the study had non-small-cell lung cancer, the leading cancer killer in the U.S.
All had tumors that had spread beyond their lungs despite treatment with an average of three other therapies.
"These are patients with very advanced disease" who have little chance of survival, says study researcher Charles Rudin, MD, PhD. He is professor of oncology and associate director for clinical research at Johns Hopkins University Kimmel Cancer Center in Baltimore.
Rudin says that he has consulted for Syndax Pharmaceuticals, the company that makes one of the drugs tested in the study.
Most patients with cancer this advanced are only expected to survive for about four months, the researchers note.
After treatment with a combination of the medications Vidaza, which is FDA approved to treat certain rare blood disorders, and the experimental pill entinostat, however, the average survival for the entire group was 6.4 months.
Doctors who wrote an editorial on the study note that this result was just shy of the same average survival (6.7 months) seen in patients treated with Tarceva, the only medication that's approved to treat patients with non-small-cell lung cancer that has spread to other organs.
The figure from the new study, however, included 11 patients who dropped out of the study before finishing a single cycle of treatment.
Among patients who finished at least one full treatment cycle, the average survival was even higher, about 8.6 months.
What's more, four of 19 patients who got chemotherapy after the experimental drug combo had dramatic responses to those treatments, "raising the hypothesis that maybe the epigenetic therapy is in some way priming the tumor for response to chemotherapy," Rudin says.
In total, seven patients who took part in the trial are still alive; two have survived for more than four years.
Two patients in the study had remarkable results.
In one patient, the cancer completely disappeared for 14 months, though she later developed a different kind of lung cancer that proved fatal.
A second patient saw tumors that had spread to his liver vanish and the primary tumor in his lung shrink.
Researchers described the drugs as well tolerated with few side effects for patients. The most commonly reported side effect was fatigue.
Despite their promising results, researchers say there's still a lot more to be learned before the epigenetic therapy becomes a mainstream treatment.
"This trial is small," Rudin says, "and these results certainly need to be confirmed in a larger study population."
Researchers say larger studies testing the drug combo are already underway.
"This is not yet a study that would in any way impact standard of care for this disease. But I think it opens up a new avenue that may be of real benefit to these patients," Rudin says.

Understanding Epigenetics

The drugs are believed to work by blocking a process that stops the activity of genes that naturally block tumor growth. In some cancers, these genes are switched off, taking out one of the body's natural defenses.
In contrast to drugs that target a specific gene or a mutation in a gene when it shows up in cancers, epigenetic therapies aim to control gene expression.
To help explain how it works, researcher Stephen A. Baylin, MD, professor and deputy director of the Kimmel Cancer Center at Johns Hopkins University, likens genes to the hard drive on a computer.
"But the hard drive needs a software package to tell it how to function and epigenetics is essentially that software package," Baylin says. Baylin says he has no financial interest in the drugs tested in the study, but that he has helped develop a blood test used in the research.
"In every patient's cancer, of every type, hundreds of genes can also be affected by abnormalities in the software package, or epigenetic abnormalities, and that's what we are theoretically trying to target," he says.

Who Will Benefit?

One key question is why some people in the study had dramatic responses to the medications when others did not.
To answer that, researchers gave 26 patients in the study blood tests to check the function of four genes that were shown in an earlier study to affect how aggressively lung cancers might spread.
If at least two of the four genes were switched off, lung cancers are more likely to recur and spread.
And indeed, in 10 patients who had at least two silenced genes, using the epigenetic drug therapy to turn those genes back on increased survival significantly compared to 16 patients whose genes weren't switched off in the first place.
"The investigators have done a great job in trying to identify specific biomarkers," Engleman says. "We need to know which patients will respond to these therapies."

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