Mutations in the Notch gene play a big role in a variety of cancers, including T-cell acute lymphoblastic leukemia. But that's not all Notch does, making this a particularly difficult target in the development of new cancer therapies.
Researchers at the University of Michigan Comprehensive Cancer Center, though, say they may have the answer to developing a Notch drug that won't trigger so many nasty side effects.
The group determined that the Zmiz1 protein sticks to Notch, causing the changes that drive cancer. But because it's separate from Notch's healthy functions, targeting the link between the protein and the gene may be the safest approach to developing a new therapy.
"If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch," says Dr. Mark Chiang, an assistant professor of internal medicine at the University of Michigan Medical School.
Chiang tested this approach in mice and determined that the treated rodents lived longer, a crude but sometimes telling indication of efficacy. Now the team plans to use X-ray crystallography tech to create a three-dimensional picture of Notch and Zmiz1 so they can create the best drug possible for breaking the two up.
"Our goal is to develop a drug to sit right between Notch and Zmiz1 that could break apart the bond. We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors," Chiang says.
Results of the study are published online in the journal Immunity.