NIH Record - National Institutes of Health

Scientists Reveal Potential New Approach to Treating Liver Cancer

A drug screening plate and a vial
NCATS scientists used drug-screening plates, like those shown here, to identify a molecule that was effective in killing liver cancer cells.

Photo:  NCATS

Scientists at NIH and Massachusetts General Hospital (MGH) have uncovered a potential new approach against liver cancer that could lead to the development of a new class of anti-cancer drugs. In a series of experiments in cells and mice, researchers found that an enzyme produced in liver cancer cells could convert a group of compounds into anti-cancer drugs, killing cells and reducing disease in animals.

Researchers suggest this enzyme could become a potential target for developing new drugs against liver cancers and perhaps other cancers and diseases as well.   

“We found a molecule that kills cells in a rare liver cancer in a unique way,” said Dr. Matthew Hall, a leader of the work at the National Center for Advancing Translational Sciences (NCATS). “It emerged from a screening to find molecules that selectively kill human liver cancer cells. It took a lot of work to figure out that the molecule is converted by an enzyme in these liver cancer cells, creating a toxic, anti-cancer drug.”

Hall, MGH liver cancer specialist Dr. Nabeel Bardeesy and their colleagues reported their results in Nature Cancer.

Bardeesy was originally studying cholangiocarcinoma, a type of liver cancer that affects the bile duct. The cancer is characterized by mutations in the IDH1 enzyme. Bardeesy’s team wanted to find compounds and drugs that might be effective against the IDH1 mutation. 

Through a collaboration with NCATS, Hall and other NCATS scientists rapidly tested thousands of approved drugs and experimental cancer agents for effectiveness in killing cholangiocarcinoma cells, with IDH1 as a target.

They found several molecules, including one called YC-1, could kill the cancer cells. Yet, when they looked to see how YC-1 was working, they discovered the compound wasn’t affecting the IDH1 mutation.

The MGH researchers showed the liver cancer cells made an enzyme, SULT1A1. The enzyme activated the YC-1 compound, making it toxic to tumor cells in cancer cell cultures and mouse models of liver cancers. In the animal models treated with YC-1, the liver tumors either had reduced growth or shrank. Conversely, they found no changes in tumors treated with YC-1 in animals with cancer cells lacking the enzyme.

Researchers examined other databases of drug screening results in compound and drug libraries to match drug activity with SULT1A1 activity. They also looked at a large NCI database of anti-cancer compounds.

They identified several classes of compounds that relied on SULT1A1 for their tumor-killing activity. 

“We think these molecules have the potential to be an untapped class of anti-cancer drugs,” Bardeesy said. “Our results suggest there could be other SULT1A1-dependent compounds with ranges of different targets. Identifying such compounds and targets on cells could have potential implications for developing other types of small molecules and drugs, not just limited to these cancers.”

The NIH Record

The NIH Record, founded in 1949, is the biweekly newsletter for employees of the National Institutes of Health.

Published 25 times each year, it comes out on payday Fridays.

Assistant Editor: Eric Bock (link sends e-mail)

Staff Writer: Amber Snyder (link sends e-mail)