A new study, published in the journal Immunity, suggests a potential new way to block one of the most common cancer-causing genes, without causing severe side effects.
The Notch gene plays a role in many types of cancer. It's the most common cancer-causing gene in T-cell acute lymphoblastic leukemia. About 60 percent of children and adults with T-cell leukemia harbor a Notch mutation. But drugs designed to block Notch have caused serious side effects such as severe diarrhea or skin cancers.
Now a team from the University of Michigan Comprehensive Cancer Center offers a potential new target to block Notch without the toxic effects. The researchers found that a protein called Zmiz1 sticks to Notch, triggering the gene to turn on its cancer function. But Zmiz1 does not impact normal healthy Notch functions.
The researchers found that mice lived longer when Zmiz1 was deleted, and they had normal body weight and no severe side effects from blocking Zmiz1.
"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," said Mark Chiang, from University of Michigan Medical School.
While the majority of kids with T-cell leukemia are cured, about 20 percent will relapse. Those kids face a grim prognosis. To date, no targeted therapies exist for these kids.
"We need to develop therapies against Notch to help kids with relapsed cancer and to cure kids with fewer toxicities or long-term effects," Chiang says. "Our current treatments may often be curative, but there can be a huge price to pay in late effects."
More research is needed before getting to this point with patients. The researchers plan to use X-ray crystallography to create a three-dimensional image of Notch and Zmiz1 in an effort to understand how they are sticking together. This would allow them to design a drug to separate the two proteins.
Based on material originally posted by University of Michigan Health System.