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health world

Promising cancer therapy is based on epigenetics

November 09, 2011|By Shari Roan, Los Angeles Times / For the Booster Shots blog
  • Medications that affect epigenetic changes helped some patients with advanced, non-small cell lung cancer.
Medications that affect epigenetic changes helped some patients with… (Associated Press )

A novel type of cancer therapy appears dramatically effective in at least some patients, researchers announced Wednesday. The two-drug medication regimen represents a new treatment approach called epigenetic therapy and signals another potential avenue to eradicate tumors.

Epigenetics explains molecular characteristics apart from DNA sequence that influence how genes are expressed. While gene mutations are known to cause cancer, epigenetic changes that turn genes on or off also affect disease development.

The new study, published in the journal Cancer Discovery, was a small, phase-2 study of 45 patients facing almost certain death from non-small cell lung cancer. The patients had advanced disease that had spread, and they had failed to respond to several rounds of chemotherapy and other treatments.

Researchers at Johns Hopkins University gave the patients a combination of the drugs azacitidine and entinostat, medications that had already been shown to benefit leukemia patients. The average group survival rate was 6.4 months compared with the average survival rate of about four months for patients receiving standard treatment.

However, eight of the patients died before they could receive a second treatment. Among the patients who had two or more treatments, survival averaged about eight months. Moreover, a few patients had dramatic responses. Seven people are still alive, with one person marking four years of survival.

The study results still need to be replicated, and many questions remain about how the drug combination affects cells. Azacitidine is thought to block an epigenetic change known as DNA methylation that could turn on genes that fight cancer.

Azacitidine is a type of chemotherapy that proved too toxic to use. But, given at very low doses in the study, patients were able to tolerate the medication. At low doses, the drug doesn't kill cancer cells -- the aim of traditional chemotherapy -- but instead appears to coax genes to switch on to fight cancerous cells.

"The idea is by giving these drugs at low doses we may affect gene expression in the tumor without killing the cancer cells, allowing the cells to reprogram and, possibly, changing their fate," said Dr. Charles Rudin, professor of oncology, associate director for clinical research at Johns Hopkins Kimmel Cancer Center and a study author.

To their surprise, researchers also found that some of patients who went on to have traditional chemotherapy after the epigenetic therapy responded much better than would have been expected for such advanced disease.

"Maybe the epigenetic therapy is priming the tumor for response to chemotherapy," Rudin said.

The epigenetic therapy appears to work well for some patients and not at all for others. Future research will be needed to determine which patients have genetic markers that predict they will respond positively to the therapy, said Dr. Malcolm Brock, associate professor of surgery and oncology at Johns Hopkins Kimmel Cancer Center and a study author.

"We are very interested in trying to pinpoint exactly which patients would benefit from this therapy," he said.

Brock looked at genetic markers that affect DNA methylation and found that patients with specific markers responded better to the therapy. That kind of test may be used in the future to predict which patients would respond.

The study is "groundbreaking," said Dr. Manel Esteller, director of the Cancer Epigenetics and Biology Program at Bellvitge Biomedical Research Institute in Barcelona. Esteller was not involved in the research.

"This is just the beginning of other drugs that target epigenetics," he said. "There are other epigenetic changes that can be targeted."

Future studies will likely test the concept on tumors or the colon, breast, brain and other organs.

A larger trial is already underway at several U.S. medical centers to examine how the therapy works in people diagnosed with early-stage non-small cell lung cancer.

"This is an incredibly exciting finding that will set off a whirlwind of research activity in the lung-cancer community," said Dr. Jeffrey A. Engleman, director of thoracic oncology at Massachusetts General Hospital, who was not involved in the study.

The research was funded in part by Stand Up To Cancer.

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