Target: ALL

A pair of St. Jude scientists have childhood cancer in their sights.

Thanks to scientists like James Downing and Charles Mullighan, the battle against acute lymphoblastic leukemia (ALL) — the most common form of childhood cancer — is being won. What 50 years ago would have been a death sentence for 95 percent of those diagnosed is now cured at the astonishing rate of 80 percent. Alas, that means 20 percent of children diagnosed with ALL are not cured. Which is where Dr. Downing (scientific director at St. Jude Children's Research Hospital) and Dr. Mullighan (an assistant member of St. Jude's pathology department) may well have taken a significant stride.

In research first published in the New England Journal of Medicine in January, Downing and Mullighan have pinpointed certain genetic changes that appear to increase the likelihood of a relapse of ALL. This is significant, in that only 30 percent of children who relapse survive the disease. The St. Jude scientists analyzed the genetic composition of leukemia cells from more than 200 patients, and discovered that 75 percent of patients who had an abnormality in a gene called IKZF1 (or "IKAROS") relapsed. IKAROS is critical for the normal development of white blood cells from stem cells. Using this information, doctors around the world have another ingredient in the recipe for preventing the all-too-deadly relapse of ALL.

"If 80 percent of ALL patients are cured," explains Downing, "that means 20 percent are resistant to the chemotherapy. Why they're resistant is an important research question. If we can understand those mechanisms by which those cancer cells are resistant, then maybe we can figure out new ways to treat them, and get rid of them. That's our strategy, to cure 100 percent of the children with ALL."

Downing acknowledges the mapping of the human genome — first announced in 2003 — as a large breakthrough in the molecular science that may someday conquer not only ALL, but many other forms of cancer. Mullighan describes the new genetic picture scientists were given with a dictionary metaphor: "Before the genome project, we were only able to detect abnormalities every million or two million letters of our DNA sequence. Now we can find changes that involve only several thousand letters."

The St. Jude scientists compared the DNA of cancer cells with the DNA of cells in a healthy person. This allowed them to, as Mullighan puts it, "weed out" normal mutations from those that are cancerous. Mullighan emphasizes that normal variations in our genetic code are what "define us as a race." It's isolating the oddities that can kill that drives the ongoing research in the fight against ALL.

A fundamental difference between childhood cancer and the kinds that strike adults is that childhood cancer manifests itself in developing tissue, and it does so quite rapidly. Downing points out the cumulative processes behind most adult cancers and the large role environmental factors (i.e. smoke, radiation, etc.) play. With childhood cancer, the attack can be frighteningly sudden. "We're getting a much better idea of the genetic hits that cause leukemia," notes Mullighan, "but we don't have a good understanding of what's causing those genetic hits. Some of them develop very early in life, even in utero. Why they're developing so early, we don't know."

The next step for Downing, Mullighan, and their peers is to utilize the new research to better predict and analyze how patients will respond to treatment, and to actually improve the methods of treatment. "The problem," explains Mullighan, "is that the treatments aren't specific for the cancer cell; they may just kill all fast-growing cells in the body. So we're trying to find genetic changes that may be suitable to make a new drug against. We'd like to give the most intensive treatment to kids with the highest risk of relapse." Adds Downing, "It's exciting times, in trying to understand the biology of these leukemias and use that in a clinical setting."

Scientists face peaks and plateaus (if not valleys) in the ongoing fight against cancer. How do they handle the letdown of a plateau after a breakthrough like the one recently at St. Jude? "That's science," acknowledges Mullighan. "Very few people maintain a sustained record of accomplishment in science for a long time. That's why we like to be doctors," he adds, with a laugh. "Something to fall back on."

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