Drugs Target Epigenetic Changes to Reprogram Cancer Cells
Research results presented at the 2012 American Association for Cancer Research (AACR) annual meeting
offer new insights into an emerging treatment approach for cancer, known as epigenetic therapy. Rather than killing cancer cells by damaging their DNA or disrupting vital communication pathways, epigenetic therapy attempts to change the behavior of cancer cells by blocking chemical changes to DNA, including a process called methylation that turns genes on or off.
When chemical tags called methyl groups attach to a DNA molecule, genes can be turned on or off. DNA methylation plays an important role in gene regulation in cancer. (Image by Christoph Bock, Max Planck Institute for Informatics)
The concept behind epigenetic treatment is to “reprogram” the network of chemical changes that affect the DNA of cancer cells, explained Dr. Jean-Pierre Issa of the Temple University School of Medicine in Philadelphia. This reprogramming can alter the activity of critical genes in cancer cells that drive their growth and survival. The treatments, Dr. Issa said, “can effectively reset DNA methylation.”
Dr. Issa led the first trial in humans to test an investigational epigenetic drug called SGI-110, which is a modified form of a methylation-blocking drug called decitabine (Dacogen). SGI-110 is more stable than decitabine, which may allow for prolonged exposure to the drug. Decitabine is approved by the Food and Drug Administration (FDA) to treat myelodysplastic syndrome (MDS), a precursor to leukemia.
Dr. Issa’s lab and researchers at Astex Pharmaceuticals collaborated to develop SGI-110, with funding from the Stand Up To Cancer initiative.
Sixty-six patients with MDS or acute myelogenous leukemia (AML) were enrolled in the trial, which tested a series of doses in two treatment schedules of SGI-110. Two patients with AML whose disease had returned after previous treatments had complete responses, and one had a partial response, Dr. Issa reported at the meeting. The patients who had complete responses had the greatest decrease in methylation and the highest levels of the drug in their circulatory system.
Treatment was generally well tolerated, with only moderate side effects. The lack of side effects makes sense, Dr. Issa explained, because “cancer cells are much more reliant on DNA methylation for survival than normal cells.”
One of the dosing regimens inhibited DNA methylation more effectively than the other, he noted, so future trials will use that dosing regimen.
Giving Cancer Cells a New Memory
Dr. Stephen Baylin of the Johns Hopkins University Kimmel Cancer Center presented findings at the AACR annual meeting from a laboratory study of decitabine and another methylation blocker, azacitidine (Vidaza). (The findings were also published March 20 in Cancer Cell.) Azacitidine is also FDA approved for the treatment of MDS.
Dr. Baylin’s team found that low doses of the drugs had antitumor effects in cell lines and in mouse models of different cancer types—including leukemia and breast and colon cancer. Post-treatment analyses of treated cells showed decreased DNA methylation and the reactivation of genes that can affect tumor growth and cell death.
The concept behind epigenetic treatment is to "reprogram" the network of chemical changes that affect the DNA of cancer cells.
The cells were treated with the drugs for only 3 days, he noted. Next, the cells were “rested for 1 to 2 weeks, and then we put them into the mice to see what the cells ‘remembered’” in terms of gene activity that influenced their behavior. Tumor growth was substantially inhibited in mice that received the treated cells compared with mice that received untreated cells, implying that the demethylating drugs had produced a “memory” antitumor response.
The drugs, Dr. Baylin continued, also appear to alter gene activity in stem cell-like cancer cells—cells that are capable of self-renewal and that studies have suggested are inherently resistant to most current therapies.
Azacitidine and decitabine were tested extensively in the 1970s and 1980s but were too toxic for patients at the high doses needed to rapidly kill cancer cells. The FDA approved much lower doses of the drugs to treat MDS, however. Low doses of the drugs have also shown efficacy
in some patients with AML. Although neither drug is FDA approved for AML, some doctors are using them off-label to treat the disease, Dr. Issa said.Dr. Baylin believes that these new findings suggest that low-dose azacitidine and decitabine may be of benefit in multiple cancers. He also presented updated results from an early-phase trial (initially reported last year) of low-dose azacitidine combined with entinostat, another epigenetic drug, for patients with advanced lung cancer. Several patients have had strong tumor responses, he reported, some of which continued even after treatment was stopped.
A number of patients in the trial, many of whom had already received multiple prior therapies, “are going on to subsequent therapies,” Dr. Baylin said, “and we have started to see some very robust responses.”
For example, four patients with advanced lung cancer who participated in the azacitidine/entinostat trial at Johns Hopkins went on to receive one of two investigational immunotherapy drugs called anti-PD1 and anti-PD-L1. Both drugs target molecules involved in blocking immune responses to tumors. Dr. Suzanne Topalian of the Johns Hopkins University Kimmel Cancer Center reported at an AACR plenary session that 3 of the 4 patients have had objective tumor responses.
A Maturing Field of Research
Although epigenetically directed therapy shows promise, there are still many unknowns, stressed Dr. Kornelia Polyak of the Dana-Farber Cancer Institute. Even though the clinical trial and the study found evidence of DNA demethylation, “it could be much more complex than that,” Dr. Polyak said.
The drugs may be having other effects, she continued. Epigenetic therapies may affect the structure of chromatin, the complex of DNA and proteins that forms chromosomes, which could cause side effects over a long period. In patients with advanced cancer, who have few treatment options, this may not be a significant concern, she noted. “But as we push these agents forward into earlier disease, it’s something we’ll need to look at very carefully,” Dr. Polyak said.
But from a clinical standpoint, she continued, demethylating agents are attractive “because even short-term treatment can have long-term effects. We’ve already seen that in MDS.”
“The field is maturing nicely,” Dr. Issa said. But more work is needed. “The [demethylating] drugs we have don’t cure patients, and we’re seeing resistance to these drugs develop.”
Dr. Baylin and Dr. Issa’s groups are studying DNA demethylating drugs in other cancer types and in combination with other therapies. “One of the biggest things we’re seeing is that these drugs are priming patients for better responses to subsequent therapies,” Dr. Baylin said.
—Carmen Phillips
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