Photo courtesy of the
University of Michigan
A new study suggests a potential way to block one of the most common cancer-causing genes without causing severe side effects.
The Notch gene plays a role in many cancers, and it’s the most common cancer-causing gene in T-cell acute lymphoblastic leukemia (T-ALL).
About 60% of children and adults with T-ALL harbor a Notch mutation.
Unfortunately, drugs that inhibit Notch can cause serious side effects, such as skin cancers.
Now, investigators have discovered a potential new target to inhibit Notch without the toxic effects.
They found that a protein called Zmiz1 sticks to Notch, prompting the gene to turn on its cancer function. But Zmiz1 does not impact normal, healthy Notch functions.
“Notch controls the genes that cause cancer, but it’s also important for normal health,” said Mark Chiang, MD, PhD, of the University of Michigan in Ann Arbor.
“The challenge is to knock out the cancer function of Notch but preserve its normal function. If you unstick Zmiz1 from Notch, the cancer cells die. And Zmiz1 seems to be selective in turning on the cancer functions of Notch.”
Dr Chiang and his colleagues found that mice lived longer when Zmiz1 was deleted. The mice had normal body weight and no severe side effects from Zmiz1 deletion.
The investigators reported these results in Immunity.
“Our goal is to develop a drug to sit right between Notch and Zmiz1 that could break apart the bond,” Dr Chiang said. “We think this would block the Notch cancer pathway without causing toxic side effects, like we see with current Notch inhibitors.”
He noted that a majority of children with T-ALL are cured, but about 20% will relapse. Those children face a grim prognosis.
“We need to develop therapies against Notch to help kids with relapsed cancer and to cure kids with fewer toxicities or long-term effects,” Dr Chiang said. “Our current treatments may often be curative, but there can be a huge price to pay in late effects.”
To further this research, Dr Chiang and his colleagues plan to use X-ray crystallography to create a 3-dimensional image of Notch and Zmiz1 in an effort to understand how they are sticking together. This could help the team to design a drug to separate the proteins.
