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Unmuffled Genes Slow Down Lung Cancer

9 November 2011 3:10 pm
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Adapted from R. A. Juergens et al., Cancer Discovery (December 2011), © American Association for Cancer Research

Responder. Tumors in a patient's lung (top), lymph nodes, and liver shrank over 8 months after he received an epigenetic drug combination. He is alive 2 years later.

A novel approach to treating lung cancer that aims to switch on dormant tumor-blocking genes has shown promise in a small clinical trial. The 45 patients on average lived a couple months longer than they would have with no treatment, and two patients' tumors almost or completely disappeared. The results suggest that so-called epigenetic drugs are worth exploring further, the authors say.

Most cancer drugs try to kill tumor cells. "Epigenetic" drugs are supposed to work differently, resetting a tumor cell's genetic activity so that it no longer divides rather than just eliminating the cell. The term epigentics refers to chemical changes to DNA that control the activity of genes, turning their expression on or off, for example; in one kind of epigenetics, chemicals called methyl groups can attach to DNA and block it from being transcribed into a protein. In many cancer types, such methylation has silenced tumor-suppressor genes.

Cancer biologists such as Stephen Baylin of Johns Hopkins University in Baltimore, Maryland, have suggested that drugs that strip the methyl groups from DNA could stop cancer cells from growing by switching these tumor-suppressor genes back on. In fact, a drug called azacytidine that demethylates DNA has been approved since 2004 for treating a type of blood cancer. However, trials in the 1970s and '80s found that azacytidine was too toxic for patients with solid tumors.

But Baylin and other Hopkins researchers recently decided to see whether azacytidine could help patients with solid cancers if given at low doses potent enough to reset DNA methylation patterns but not kill cells. Led by oncologist Charles Rudin, the team identified 45 patients with late-stage lung cancer for which other therapies had failed and gave them low doses of azacytidine and another epigenetic drug that opens up the protein packaging around DNA.

The study was a modest success. The average patient lived 6.4 months--only 2 months longer than they would have with no treatment. However, two patients' tumors nearly or completely vanished. Although their cancer later returned, one of these patients is still alive after 2.5 years. And four patients who didn't do well on epigenetic therapy responded strongly to subsequent standard cancer drugs; two have lived 4 years, well beyond what was expected given their cancer.

Why did some patients fare much better than others? The Hopkins group speculates the reason is that only some patients' tumors were driven by epigenetics. They tested tumor DNA from 26 of the 45 patients for four genes that, when methylated, predict that a lung tumor will soon grow back after surgery. Patients whose tumors had at least two methylated genes before treatment and later lost the methyl groups lived on average 10 months—4 months longer than patients without this pattern, according to the study, published today in Cancer Discovery.

"It's not a home run, but it's a real entry into this area," Baylin says. The results suggest that doctors could test patients' gene-methylation patterns to find out if their tumors could be treated by the epigenetic drugs, he says. His team is also intrigued by the suggestion that epigenetic drugs can prime tumor cells to respond better to other drugs, a possibility they hope will be tested in another trial.

Two researchers not involved with the study described it as "groundbreaking" during a media briefing today. "I think that this is an incredibly exciting finding and will set off a whirlwind of activity, of research in the lung cancer community," said oncologist Jeffrey Engelman of Massachusetts General Hospital in Boston.

Others are cautious. Molecular biologist Frank Lyko of the German Cancer Research Center in Heidelberg agrees that the study "strongly suggests" that the epigenetic drug combo works on lung cancer. But he says more precise measurements of the patients' tumor-methylation patterns are needed to show definitively that the drugs worked through epigenetic effects and not some other mechanism. The assay results reported in the paper, he says, are not "convincing."

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