November 14, 2011

Combo ‘epigenetic’ therapy may restore anti-cancer gene activity

A new type of therapy aimed at reversing the gene silencing that promotes cancer-cell growth has shown promising results in a small clinical trial conducted by researchers at the Johns Hopkins Kimmel Cancer Center. Forty-five late-stage lung cancer patients who received a two-drug combination designed to restore anti-cancer gene activity survived about two months longer than the expected four months, and two patients showed complete or near-complete responses despite having progressive disease after multiple standard therapies.

In the study, reported in Cancer Discovery Nov. 9, the researchers treated non-small-cell lung cancer patients with a combination of the drugs azacitidine and entinostat. Azacitidine removes methyl groups from genes; entinostat inhibits histone deacetylation, a closely related process that also contributes to gene silencing.

“We hope these results lead to a larger, more definitive clinical trial of this drug combination,” said Charles Rudin, a professor of oncology and director of the Upper Aerodigestive Cancer Program at the Kimmel Cancer Center. Rudin led the team of physicians and cancer biologists who conducted the study, which is believed to be one of the first to show promising results for “epigenetic” anti-cancer therapies in solid tumors.

Johns Hopkins researchers previously tested the drug combination in leukemia patients. Laboratory results suggest that epigenetic treatments aim not to kill cancer cells directly but instead may reprogram their patterns of gene expression so that they lose their capacity for uncontrolled growth. A normal cell has a specific pattern of gene expression, in which some genes are active and others are suppressed, and a derangement of this pattern frequently contributes to cancer, in part by silencing genes whose activity would normally stop a cell from becoming cancerous. Cancer cells also have permanent genetic mutations, which cannot be undone with drugs, but in many cases they may achieve similar cancer-promoting effects through mutations and epigenetic gene silencing.

The trial was based in part on the results of a study reported in the New England Journal of Medicine in 2008 by a group of Johns Hopkins researchers, led by Malcolm Brock and including cancer epigenetics experts Stephen Baylin, the Virginia and D.K. Ludwig Professor for Cancer Research and deputy director of the Kimmel Cancer Center; and James Herman, a professor of oncology. In that study, the researchers found that early-stage non-small-cell lung cancer is much more likely to recur after surgery if the tumor and nearby lymph nodes contain gene-silencing markers known as methyl groups on at least two of four key genes.

“We showed in the late 1990s that if you got rid of the abnormal DNA methylation first, and then used a histone deacetylase inhibitor, you could enhance the re-expression of these abnormally silenced genes,” Baylin said.

The new study enrolled 45 patients with metastatic non-small-cell lung cancer that had progressed after earlier standard therapies. Initial tests of the drugs in 10 patients established that the planned doses did not cause unacceptable side effects, and eventually another 35 patients were treated. Each received azacitidine on nine days and entinostat on two days per month.

The trial had an “open label” design, meaning that all patients received the treatment and there was no control group receiving a placebo. Such trials are often used in early clinical investigations of cancer drugs, Rudin said, because the patients who receive them typically have life expectancies of six months or less and have relatively few good treatment options.

As noted earlier, median survival of all patients treated with the combination epigenetic therapy was two months longer than the four months normally expected. Patients who showed signs of gene methylation reversal in at least two of four key genes had better survival than the rest, and two patients experienced dramatic tumor shrinkages.

“One patient’s tumor appeared to have a complete response,” Rudin said. That patient, who formerly had smoked, survived for nearly three years before succumbing to a different lung tumor. In another patient, a man whose metastasizing lung tumors had spread to his liver, the epigenetic treatment cleared his metastases and markedly reduced his original lung tumor. “That patient is, in fact, still alive, two and a half years after getting the epigenetic therapy,” Rudin said.

In addition to showing that the combination epigenetic therapy is well-tolerated and can be effective, the study, Rudin said, suggests that the silencing status of these four key genes may represent a “biomarker” of benefit from the combination therapy in non-small-cell lung cancer. It also suggests, he said, that the combination of azacitidine and entinostat can show favorable epigenetic effects at much milder doses than the cell-killing doses at which azacitidine was originally used in cancer patients.

One further hopeful result of the study was the observation that following their epigenetic drug therapy, a number of patients showed unexpectedly strong responses to further treatment with standard chemotherapies. “This raises the possibility that the epigenetic treatment is having a delayed effect, or is even sensitizing patients’ tumors in a way that makes them more vulnerable to subsequent therapies,” Baylin said.

The Johns Hopkins researchers said that they are approaching the manufacturers of the drugs to develop additional studies. One such study has been launched, testing this combination in patients with early-stage cancers that have been surgically removed.

The study was funded by the National Institutes of Health SPORE Program, the Flight Attendant Medical Research Institute and a Stand Up to Cancer Award from the American Association for Cancer Research in association with the Entertainment Industry Foundation.

Additional scientists contributing to the research were Rosalyn A. Juergens, formerly of the Johns Hopkins Kimmel Cancer Center and currently at McMaster University; Brock, John Wrangle, Frank P. Vendetti, Sara C. Murphy, Ming Zhao, Barbara Coleman, Rosa Sebree, Kristen Rodgers, Craig M. Hooker, Noreli Franco, Beverly Lee, Salina Tsai, Michelle A. Rudek and Herman, all of Johns Hopkins; Igor Espinoza Delgado, of the National Cancer Institute; and Steven A. Belinsky, of the Lovelace Respiratory Research Institute.

Juergens and Rudin previously consulted for Syndax Pharmaceuticals, manufacturer of entinostat. Herman has previously consulted for MDx Health, which licensed Johns Hopkins–invented technology on a methylation-specific PCR method to identify gene methylation status; Herman and Brock have research support from MDxHealth; and Herman, Brock and Baylin hold a patent licensed to MDx Health. These arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.