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Genomics Leads to New Leukemia Treatment
By Nancy Touchette

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One of the more sobering scientific advances of the 20th century was the realization that cancer is not a single disease but perhaps hundreds of diseases and that there would be no single cure.

Leukemia cells that overexpress the FLT3 gene (labeled pink) compared to cells with normal FLT expression.

Then along came genomics with the hope that it would reveal the molecular origins of cancer and other diseases. Doctors might someday tailor treatments to individuals based on the molecular profiles of their diseases. But when and how that might happen has been anyone's guess.

Now, recent studies of leukemia in children suggest that the era of genome-based medicine may be closer than many had imagined.

Using gene chips, or DNA microarrays, to measure gene activity, researchers have characterized a distinct type of leukemia called mixed lineage leukemia, or MLL. They found a gene that is overactive in most MLL patients and have developed a potential new drug that targets the product of the renegade gene. The drug, which kills leukemia cells in mice, is expected to enter clinical trials next year.

MLL cells (labeled blue) injected in mice spread throughout the body in the absence of treatment (top). Treatment with PKC412 after one week halts the spread of cancer (bottom).

The advance, although preliminary, epitomizes the future direction of cancer research.

“This is just the tip of the iceberg,” says Scott A. Armstrong of the Dana Farber Cancer Institute in Boston , who leads the research. “While we always try to temper our excitement, it's not too hard to believe that we will soon be able to tailor individual therapies to specific diseases. This is something we don't do well now.”

Armstrong and his colleagues study leukemia in children and have been particularly interested in acute lymphoblastic leukemia, or ALL, the most common form of childhood cancer. Although the disease can be successfully treated in more than 80 percent of patients, some forms of the disease are resistant to treatment and the survival rate is less than 50 percent.

To better classify subtypes of ALL, the researchers studied patterns of gene activity in patient samples using DNA microarray technology. They discovered that one form of ALL, marked by rearrangements of a gene on chromosome 11, had a unique pattern of activity, or genetic signature. This led the researchers to propose a new subtype of leukemia, which they call mixed lineage leukemia, or MLL.

When Armstrong and his colleagues looked closer they noticed that one of the genes, called FLT3, is especially active in MLL patients. The gene is also active in an adult form of leukemia, acute myelogenous leukemia (AML).

Researchers studying that cancer had already discovered a drug that targets the FLT3 protein. Armstrong and his colleagues then decided to see if the drug is effective against MLL cells.

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The researchers found that when MLL cells are injected in mice, leukemia spreads throughout the body within weeks. But if the mice are treated with the drug, the cancer cells are effectively killed.

The new leukemia drug is currently being tested in clinical trials against AML in adults. Armstrong and his colleagues are in the process of designing a clinical trial to test the safety and efficacy of the drug in children with MLL and hope to launch the trial by spring of 2004.

Todd Golub, Armstrong's colleague at Dana Farber, says the study illustrates a new way of looking at cancer.

“To begin to make a dent in cancer, two things have to occur,” says Golub. “We have to be able to classify cancers based on their molecular profiles, not on which organ in the body they appear.”

Not all breast cancers are the same, for example. But physicians have been treating most breast cancers the same way, even though they might have very different molecular causes.

Once cancers are accurately classified, the second step can occur: develop anti-cancer drugs that specifically block the molecules at the root of disease.

“The thinking that we can have one drug against all cancers is over,” says Golub. “We're moving towards molecularly inspired medicine.”

. . .


Armstrong , S.A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genetics 30 , 41-47 (January 2002).

Armstrong , S.A. et al. Inhibition of FLT3 in MLL: Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 3 , 173-183 (February 2003).


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