Liver cancer finding leads to new antitumor therapy
28 March 2023
Researchers at the NIH and Massachusetts General Hospital in Boston say they have uncovered a potential new approach against liver cancer that could lead to the development of a novel class of anticancer drugs. In a series of experiments in cells and mice, the team found that an enzyme produced in liver cancer cells could convert a group of compounds into anticancer drugs, killing cells and reducing disease in animals.
The researchers, who published their study “SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers” in Nature Cancer, suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps other cancers and diseases as well.
A group at the NIH’s National Center for Advancing Translational Sciences (NCATS) used the Center’s drug screening capabilities, including drug screening plates like those shown here, to identify a molecule that was effective in killing liver cancer cells. Researchers determined that a specific enzyme was key to turning the molecule into a potential anticancer drug. [NCATS]
“Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection,” write the investigators.
“Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1.
“Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class.“These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.”
“We found a molecule that kills cells in a rare liver cancer in a unique way,” said translational scientist Matthew Hall, PhD, one of the leaders of the work at NIH’s 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, anticancer drug.”
Results stemmed from a successful collaboration
The finding stems from a collaboration between Massachusetts General Hospital and NCATS researchers. Nabeel Bardeesy, PhD, a liver cancer specialist at Massachusetts General Hospital, 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 their 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 Massachusetts researchers showed that 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, the researchers found no changes in tumors treated with YC-1 in animals with cancer cells lacking the enzyme.
The 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 National Cancer Institute database of anticancer compounds for additional possibilities to test for their activity with the enzyme.
They identified several classes of compounds that relied on SULT1A1 for their tumor-killing activity. Using computational methods, they predicted other compounds that also likely were dependent on SULT1A1.
The scientists suggest their findings have broader implications for developing new anticancer drugs. “We think these molecules have the potential to be an untapped class of anticancer drugs that depend on SULT1A1 for their activity against tumors,” Bardeesy said.
The researchers see YC-1 and similar molecules as prototypes for developing compounds that could be effective against important proteins on cells. Modifying different parts of these molecules could make them more specific for such proteins. The researchers point to the creation of a “toolkit of SULT1A1-activated molecules” that could affect many different targets.
“We knew SULT1A1-dependent drugs had already been identified,” explained Bardeesy. “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. This might become a new approach for some diseases.”
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