Researchers identify common mutation in T-cell acute lymphocytic leukemia

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Researchers at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) have made a breakthrough discovery, identifying a common mutation in T-cell acute lymphocytic leukemia (T-ALL), an important form of cancer in children and adolescents.

The effects of the mutated gene, called NOTCH1, can be inhibited by a type of drug designed to treat Alzheimer’s disease patients, providing researchers with hope that they can now halt this form of leukemia with a new, very specific therapy. Because these drugs have already been under development for several years, a clinical trial to test it in leukemia patients will be possible in the near future.

The research will appear in the October 8, 2004 issue of the journal, Science.

“This discovery is significant because first, it tells us that NOTCH1 mutations are very important in all forms of T-ALL and secondly, gamma secretase inhibitors, a class of drugs known to ‘turn-off’ abnormal NOTCH1 activity caused by the mutation, are already in the pipeline,” said senior author, Jon C. Aster, of the Department of Pathology at BWH. “We are very hopeful that these drugs will prove to be a safe and effective treatment for T-ALL in the next year or so. Our story could prove similar to the one that’s played out with another recently developed cancer drug, Gleevec, which works in a very specific way on tumors harboring other kinds of cancer-causing mutations.”

While chemotherapy now cures about 75 percent of T-ALL patients, 25 percent succumb to their disease and the current chemotherapy regimens are toxic. According to the researchers, gamma-secretase inhibitors may be less toxic because they target mutated NOTCH1, which is only present in the cancer cells of T-ALL patients.

The normal NOTCH1 receptor creates signals that allow blood stem cells to develop into T cells, a type of white blood cell responsible for fighting infection. When this signal is over-activated, it creates too many T-cells, the first step on the road to cancer. In this study, the BWH researchers used gamma-secretase inhibitors to shut down NOTCH1 in T-ALL cells. They found that some cell lines stopped growing when treated with the drugs. Further work showed that these cell lines often had mutations in NOTCH1 that caused it to be overactive.

To see how frequent these mutations were, the team collaborated with Dana-Farber researchers to look at 96 tissue samples from T-ALL patients. They discovered mutations causing NOTCH1 over-activity in nearly 60 percent of all tumors, verifying initial laboratory results and suggesting that NOTCH1 mutations will prove to be the most important cause of this type of cancer.

“This work moves NOTCH1 to the center of understanding the root causes of T-ALL,” said Aster. “The findings also make us curious to know if abnormal NOTCH proteins might be found in other kinds of human cancer. Together with our colleagues at the DFCI, we are searching for similar mutations in tumors such as breast, prostate, and brain cancer.”

In the wake of the findings, Dana-Farber researchers are planning a small Phase I/II clinical trial in patients with T-cell ALL to test the safety of a NOTCH1 pathway-inhibiting drug. Led by Daniel J. DeAngelo, MD, PhD and Lewis Silverman, MD, the trial will include about 20 patients, both children and adults, whose T-cell ALL has relapsed after previous therapy achieved a remission. The scientists expect the trial to begin within the next several months. Measurements of biochemical changes in the volunteers will be made to look for signs of the drug's activity.

Jon C. Aster, MD, of BWH, is the paper’s senior author. Andrew P. Weng MD, PhD, now of the British Columbia Cancer Agency, Woojoong Lee, Stephen C. Blacklow, and Cheryll Sanchez-Irizarry of BWH along with Adolfo A., Ferrando, Lewis B. Silverman, MD, John P. Morris IV and A. Thomas Look, MD of DFCI are co-authors.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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