New Hope for an Old Drug on Orlando Medical News

New Hope for an Old Drug

By: J.L. WEBB

Once Discontinued, DFMO May Combat Neuroblastoma

Two of Orlando's leading pediatric oncologists/hematologists are responding with guarded hope that preliminary research aimed at preventing one of the deadliest cancers in children will be beneficial.

A study by scientists at the Florida campus of the Scripps Research Institute in Jupiter suggests that the drug compound a-difluoromethylornithine (DFMO) may, in limited doses, thwart the recurrence of neuroblastomas in young children. The study, published in the January issue of Cancer Research and supported by the National Institutes of Health, showed that in animal models DFMO impeded the production of a gene that promotes malignant tumors.

However, because use of DFMO as a cancer therapy was discontinued more than 30 years ago due to concerns about toxic side effects in patients, the Scripps study is being viewed with cautious optimism by those on the front lines of pediatric oncology.

"Is it a breakthrough? (That's) hard to say. I want to know what side effects it is causing," said Don Eslin, MD, who is an attending physician of pediatric hematology/oncology at M.D. Anderson Cancer Center Orlando. But Eslin was quick to temper his skepticism with praise. "Anything that we can find, particularly for this disease, we're always interested to find out more. It's one of the most devastating cancers … and anything we can do to improve the outcome – that is not going to cause long-term side effects – is something that should be pursued," said Eslin, 45.

Indeed, neuroblastoma is deadly. "Even though it is the most common solid tumor in children, it is also one of the ones we have the lowest cure rates on," Eslin said. "Cure rates in pediatric cancer, in general, are fairly high, especially as compared to adult cancers. But in this one we still have a hard time curing it. Cure rates are, at best, close to 50 percent, but that is very optimistic for the most aggressive forms of this disease," he said.

That said, Eslin said the dilemma is "We can get 85 to 90 percent of children (with neuroblastoma) into remission, meaning they get through all the therapy and there is no evidence of the disease. (But) the problem is there is a high risk of it coming back. And when it does come back, it is almost universally fatal. Cure rates for relapsed disease are... probably less than 5 percent. That makes it difficult (because) nearly half of the kids who get through their therapy eventually relapse," Eslin said. "That is why there is such a focus on prevention and trying to find something that can keep it from coming back."

According to the American Cancer Society, neuroblastomas start in early nerve cells of the sympathetic nervous system, so they can be found anywhere along that system. Most begin in the adrenal glands, the abdomen, the chest and pelvis. Rarely, they are in the brain. It usually occurs in infants and young children and is very seldom found in children older than 10 years. Neuroblastoma accounts for about 10-12 percent of all cancers in children.

What the Scripps study examined is whether the re-emergence of those tumors can be inhibited by administering DFMO and letting it attack the genes and enzymes that are known to promote cancerous growth.

The Scripps Institute explained the complex molecular connection in this manner:

The best-known genetic alteration involved in neuroblastoma is the amplification of the proto-oncogene—a molecule that when overexpressed can cause cancer—called MYCN. Amplification of MYCN occurs in about 20 percent of all

neuroblastoma and is associated with the high-risk form of the disease. Targeting this and related genes directly might be therapeutically tempting, the study noted, but highly problematic because the oncoproteins they produce are also required for the growth of most normal cell types.

Scripps researchers focused on inhibiting ornithine decarboxylase (Odc), a protein that contributes to cancer cell growth and that is a target of the proto-oncogene MYCN. Increased levels of Odc are common in cancer, and forced Odc expression in animal models has been shown to lead to increased tumor incidence. Recent findings have shown that Odc overexpression also is an indication of poor prognosis in neuroblastoma. DFMO inhibits the activity of Odc.

To test the effect of DFMO on preventing neuroblastoma, the study used a transgenic mouse modeled after the MYCN-amplified neuroblastoma in humans.

"We were able to prevent neuroblastoma caused by MYCN, delaying the onset and incidence of this tumor type," said John Cleveland, PhD, and chair of the Scripps Florida Department of Cancer Biology. "What's even more compelling, we used low doses of the drug, and DFMO only had to be given for a moderate amount of time to prevent cancer," he said.

"Our study offers a strong suggestion to the clinical cancer community that they should keep an open mind about the Odc-polyamine pathway, and that this … might represent a novel therapeutic angle to tackle this malignancy." Cleveland said. "While there are valid safety concerns about giving DFMO to pediatric patients suffering from advanced stage MYCN-amplified neuroblastoma, it may be time to revisit the issue as our study showed that transient treatment with DFMO is sufficient to provide chemoprevention and may show benefit for this otherwise lethal malignancy."

Another M.D. Anderson specialist said, "the time is right for this type of study.

There ought to be more and more studies like this. I don't know if it's going to be successful; only time will tell. But I think this is the kind of study that is called for now," said Vincent Giusti, MD, also an oncologist/hematologist in pediatrics at the hospital. "Up until recently, a lot of the work in oncology has been with chemotherapy, and many children have been cured as a result. But there has been a certain amount of toxic side effect. I think more targeted treatment like this is really the way to go," said Giusti, 70. He and Eslin, his colleague at M.D. Anderson, recently received the "2008 Extraordinary Service for Children with Cancer" award from the BASE Camp Children's Foundation. Giusti said, "We've really reached a plateau in chemotherapeutic agents. You can't go much higher with the doses because (of) the toxicity … If one can find out, on a molecular level, a target that can kill off some of these tumors, that is the way to go."

"There haven't been too many advances in terms of targeted therapy," Giusti said. "People are really working on it and (the Scripps study) would appear to be an example of that."