• 4/3/2007
  • Houston, TX
  • Eric Berger
  • Houston Chronicle (chron.com)

As they completed the “book of life” earlier this decade, scientists with the Human Genome Project declared they had struck upon the path leading toward eventual cures for most diseases.

By scribbling down all 3 billion DNA letters of the genetic code, the scientists reasoned, they could ferret out the defective genes in sick patients that explained why diseases such as cancer flourished and ultimately killed their hosts.

But less than a decade later, a related science called epigenetics may have begun eclipsing traditional genetics. In epigenetics, it is factors such as diet and smoking, rather than inheritance, that influence how genes behave.

A deepening understanding of this process has led to the development of drugs to rehabilitate cancer cells — by wiping away their bad memories — instead of bombing them into submission.

“There are more people working now on the epigenetics of cancer than the genetics of cancer,” said Jean Pierre Issa, a professor at the University of Texas M.D. Anderson Cancer Center.

That’s a claim not every cancer researcher would support, but it’s clear that interest in epigenetics has skyrocketed in recent years. A decade ago, at major cancer meetings, there would be a handful of presentations on epigenetics. Today there are hundreds. And epigenetic therapies now have moved beyond the lab and into the clinic, treating patients.

“It’s impossible to pick up any scientific journal today and not find at least one epigenetics paper,” said Peter Jones, director of the Norris Comprehensive Cancer Center at the University of Southern California and a pioneer in epigenetics research. “The growth has been explosive.”

So, what’s all the fuss about?

Cancer is a disease of malfunctioning genes.

Like a gene mutation, epigenetics also may cause a gene to break down, or begin doing bad things, such as turning a healthy cell into a cancerous one. In epigenetics, however, the DNA letters of genes are not changed or mutated. Instead, some other external force, typically a tiny hydrocarbon molecule, bonds with a healthy gene and stops it from functioning.

Among the most common of these epigenetic “silencers” is a methyl hydrocarbon chemical in the body, which attaches itself to the DNA inside cells. It still isn’t entirely clear why this methylation occurs.

Scientists have determined, however, that the process can be triggered by any number of environmental factors, such as a consistently poor diet, smoking, even aging. It is, perhaps, no coincidence that those are among the leading risk factors for cancer.

A patient cannot change his or her genes. But there already are drugs available that will strip epigenetic tags — such as methyl groups — away from DNA. And that’s the critical difference for cancer researchers.

It’s one thing for a geneticist to identify a gene that gives rise to a particular form of cancer. It’s quite another to alter the mutated gene. That was the hope of gene therapy, but that has had limited success. Epigenetic therapy, on the other hand, already has had some successes, and the promise of more.

A success story

Nancy Stanley is one of the early successes.

About two years ago, Stanley, 71, traveled from Hitchcock to Huntsville, Ala., for a granddaughter’s graduation from high school. Once there, she felt weak and turned pale. Upon returning home, she went to the University of Texas Medical Branch at Galveston, where she received several blood transfusions and was diagnosed with myelodysplastic syndrome, a deadly precursor to leukemia.

Stanley, the former medical records director at the the Harris County Jail, sought a second opinion at M.D. Anderson.

There she found Dr. Hagop Kantarjian, chair of the institution’s department of leukemia. He was initiating a trial of decitabine, a drug rejected for chemotherapy in the 1970s because of its toxicity. Working with Issa, Kantarjian recognized the drug’s epigenetic potential — it strips away the DNA methyl tags even at lower, safe doses given over longer periods of time.

Stanley joined the clinical trial and now is in remission.

“I feel good, and I have never had any side effects, no nausea,” she said. “I still have my hair and my energy. I’m 71, and I’m still running.”

The overall trial was a success, too. Forty percent of participants went into complete remission, and nearly another third derived some clinical benefit from the medicine, according to Kantarjian.

Issa described epigenetics as a departure from the normal war on cancer, an all-out assault on malignant cells with radiation and toxic drugs. Instead of killing the cancerous cells, what if the pattern of their epigenetic tags could be reset to that of the time of their birth?

“It’s like the difference between war and politics,” Issa said. “Instead of bombing the cancer cells, we’re trying diplomacy.”

The trial of decitabine was a proof of principle, a clear indicator that the epigenetic approach could work. With its recent approval by the FDA, three epigenetic drugs now are on the market for various types of cancer.

Hurdles remain. It’s easier to treat liquid tumors — those in which blood cells turn cancerous as in Stanley’s ailment — with epigenetic therapies because it is easier to deliver the drug directly to the troublesome cells. But solid tumor diseases, such as cancers of the colon, head and neck, also have been shown to be affected by DNA methylation, so the potential is there.

M.D. Anderson is conducting 17 clinical trials to test the merit of epigenetic drugs.

“This is the beginning of a new era of research,” Kantarjian said. “Epigenetic therapy is going to have a very broad therapeutic role over the next 5 to 10 years in a large number of cancers.”

Epigenetics has had an impact in other medical fields. It helps answer the question of how one identical twin might develop an illness such as schizophrenia and another be perfectly healthy. And then there’s the mystery of pregnant mothers.

For a long time, scientists understood that the diet of mothers-to-be can be critical to the chances that their offspring will acquire various diseases.

A few years ago, a team of researchers began feeding dietary supplements to obese, yellow mice who birthed brown, lean babies. The scientists determined the diet had silenced a gene in the offspring that carried a predisposition to obesity, diabetes and cancer. The supplements shut down the gene without altering the DNA sequence.

“That study, I think, helped bring attention to the fact that there’s more going on here than just basic genetics,” said Robert Waterland, an assistant professor of pediatrics at Baylor College of Medicine, and a co-author of the mice study.