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.