For years, scientists have been attempting to turn off Notch, a common cancer-causing gene, without much success. Now, University researchers may have discovered a solution.
A new study focused on Notch was led by Mark Chiang, assistant professor of internal medicine in the Medical School. Notch is heavily involved in T-cell leukemia, a cancer commonly found in children, and is also involved in breast cancer, colon cancer, melanoma and other lymphomas. In the past, Chiang said, all drugs aimed to target Notch have been associated with serious and even life-threatening side effects. This motivated his team to find a safer way to target the gene.
Chiang said targeting Notch has been particularly difficult because the gene also has beneficial functions within the body.
“It’s been very hard to target Notch because Notch not only has cancer causing-functions, but also important normal functions like keeping your intestines healthy or preventing you from getting cancers,” Chiang said. “If you simply block off Notch functions, yes you can kill some cancer cells, but then you have diarrhea — that can be life-threatening — and also second cancers.”
Chiang said the team wanted to investigate exactly what activates Notch’s cancer-causing activities. The team discovered a protein called Zmiz1, which sticks to Notch and turns on the cancer-causing functions. When the protein was separated from Notch in mice, Chiang said mice did not experience side effects typically associated with Notch-inhibiting drugs.
“If we try to break the interaction between or unstick Zmiz1 from Notch, then we can actually cause tumor regression,” he said. “This may be a way to kill cancer cells but without the major toxicities of Notch inhibitors.”
LSA junior Emily Liu, who worked on the project with Chiang, said a challenge of the research was targeting the cancerous signals of Notch without harming its other functions. She added that discovering the Zmiz1 protein may be the key to ridding Notch of its cancer functions.
“My project focused on attempting to inhibit the coactivator, Zmiz1, and to see the effects it has on physiology with mouse models,” she said. “We looked at the impact and toxicity there. What we found was there was no significant effect on the intestinal toxicity when we inhibited the coactivator, suggesting that it is selective for the cancer signals of Notch.”
Chiang said making a drug applicable to humans is the most important next step. He plans to do so by creating a three-dimensional image that will show how Zmiz1 sticks to Notch. This way, Chiang can discover how to separate the protein from the gene in humans.
“Once we have this three-dimensional image we can figure out ways to design a drug that could slip in between the two proteins and break the binding apart,” Chiang said. “That’s one of the major things we’re trying to figure out — how to get a three-dimensional image to help us make drugs to actually break this interaction.”
Though this research is primarily focused on Notch-involved cancers, Chiang said it could have implications for treating other cancers as well and said he hopes to investigate whether or not Zmiz1 plays a role in cancers that aren’t impacted by the Notch gene.
“We’ve been really focused on Notch-dependent tumors, but you also have a lot of Notch-independent cancers,” Chiang said. “We’re actually looking into that — to see whether or not our protein may be important for other non-Notch functions. That’s a good area of investigation right now.”
Liu said she believes the research will have a significant impact on cancer treatment in the future.
“There’s a lot of implications for therapy and using our protein or other proteins in that pathway as targets for drugs,” she said.