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 tumours 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.

“Prior to this study, NOTCH1 mutations were thought to be quite rare in T-ALL.  Based on its central importance in normal T cell development, however, we suspected NOTCH1 might play a much broader role in this disease.  We knew the gamma-secretase inhibitors would be useful to address this possibility because we had previously published a study showing their remarkable potency at stopping the growth of T-ALL cells in the lab,” said Dr. Andrew Weng, lead author, now with the BC Cancer Agency in Vancouver, Canada. 

To see how frequent these mutations were, the team collaborated with Dana-Farber Cancer Institute (DFCI) researchers to look at 96 tissue samples from T-ALL patients.  They discovered mutations causing NOTCH1 over-activity in nearly 60 percent of all tumours, 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.”

Weng is now conducting research at the BC Cancer Agency to understand how NOTCH1 signals cause tumour cells to grow. “The NOTCH1 signal is delivered to the nucleus of the cell where it turns on the expression of other genes.  However, we still don’t know which genes are implicated, and how they contribute to uncontrolled tumour growth.”