Target found to block Notch cancer pathway without side effects

Researchers have discovered a potential target that could improve Notch inhibitors and also eliminate their problematic side effects for patients with lymphoblastic leukemia. 

Notch inhibitors have been poorly tolerated in clinical cancer trials because Notch signals are crucial for intestinal homeostasis. Notch inhibitors might also promote cancer because the Notch gene can act as a tumor suppressor. Thus, drugs designed to block Notch have caused serious side effects, such as severe diarrhea and skin cancers.

“Notch controls the genes that cause cancer, but it’s also important for normal health. The challenge is to knock out the cancer function of Notch but preserve its normal function,” said the study’s lead author Mark Chiang, MD, PhD, Assistant Professor of Hematology at the University of Michigan Medical School, in Ann Arbor, MI.

In this study, Dr. Chiang and colleagues described the protein Zmiz1, which sticks to the Notch gene and triggers it to turn on its cancer function. They determined that Zmiz1 is important for T-cell development and controls the expression of certain Notch target genes, such as Myc.

Targeting the Notch-Zmiz1 interaction might combat leukemic growth while avoiding the intolerable toxicities of Notch inhibitors, the researchers suggested.

In experiments in mice, the researchers deleted Zmiz1, which impaired the initiation and maintenance of Notch-induced T-ALL. The mice not only lived longer, but had normal body weight and no severe side effects from the lack of Zmiz1. Results of the study were published online October 28, 2015 in the journal Immunity.

“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 said.

“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,” Dr. Chiang said.

Notch is the most common cancer-causing gene in T-cell acute lymphoblastic leukemia (T-ALL). About 60% of children and adults with T-ALL have a Notch mutation. While the majority of children with T-ALL are cured, about 20% will relapse. To date, no targeted therapies exist for these children.

“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.”

More research is needed before such a therapy can be tested in clinical trials. For now, Dr. Chiang and his colleagues plan to use X-ray crystallography to create a three-dimensional image of Notch and Zmiz1 in an effort to understand how they stick together. This would allow them to design a drug to separate the two proteins.