Press release
Monday, March 13, 2023
Findings from cell and mouse studies may have implications for the development of a new class of cancer drugs.
Scientists from the National Institutes of Health and Massachusetts General Hospital in Boston have discovered a potential new approach to liver cancer that could lead to the development of a new class of cancer drugs. In a series of experiments on 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.
The researchers suggest that this enzyme could become a potential target for the development of new drugs against liver cancers, and perhaps against other cancers and diseases as well.
“We have found a molecule that kills rare liver cancer cells in a unique way,” said translational scientist Matthew Hall, Ph.D., one of the leaders of the work at the National Center for Advancing Translational Sciences (NCATS) from the NIH. “It emerged from a screen 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 cancer drug.
Hall, Nabeel Bardeesy, Ph.D., a liver cancer specialist at Massachusetts General Hospital, and colleagues reported their findings March 13 to nature cancer.
The discovery stems from a collaboration between researchers at Massachusetts General Hospital and NCATS. Bardeesy was originally studying cholangiocarcinoma, a type of liver cancer that affects the bile ducts. 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 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 the target.
They discovered that several molecules, including one called YC-1, could kill cancer cells. Yet when they looked to see how YC-1 worked, they found that the compound did not affect the IDH1 mutation.
Massachusetts researchers have shown that liver cancer cells make an enzyme, SULT1A1. The enzyme activated compound YC-1, making it toxic to tumor cells in cancer cell cultures and mouse models of liver cancer. In animal models treated with YC-1, liver tumors had either reduced growth or shrinkage. Conversely, the researchers found no change 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 examined a large database of cancer-fighting compounds from the National Cancer Institute for additional opportunities to test 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 were also likely dependent on SULT1A1.
“Once we found YC-1 activated by SULT1A1, it made us wonder, ‘What other compounds are active and can kill cells by the same mechanism?’ said Hall. “Can we identify other compounds in development and demonstrate that they were also active due to SULT1A1 activation? The answer was yes. We found other compounds with the same mechanism of action than YC-1.
The scientists suggest that these findings have broader implications for the development of new cancer drugs. “We believe these molecules have the potential to be an untapped class of anticancer drugs that depend on SULT1A1 for their activity against tumors,” Bardeesy said.
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 these proteins. The researchers talk about creating a “toolbox of SULT1A1-activated molecules” that could affect many different targets.
Such a toolbox is made up of hundreds of known molecules. In theory, the toolkit covers many types of enzymes, called sulfotransferases, which are active in different tissues of the body. For example, in addition to SULT1A1, the human sulfotransferase SULT4A1 is active in the brain. It can activate a subset of the toolbox molecules. This could be useful in the development of specific drugs for brain cancers.
“We knew that SULT1A1-dependent drugs had already been identified,” Bardeesy said. “Our results suggest that there may be other SULT1A1-dependent compounds with different target ranges. Identifying these compounds and targets on cells could have potential implications for the development of other types of small molecules. and drugs, and not just limited to these cancers. It could become a new approach for certain diseases.
This work was supported by the MGH Fund for Medical Discovery Award; the Cholangiocarcinoma Foundation Christopher J. Wilke Memorial Fellowship; NCI 1K99CA245194-01, V Foundation for Cancer Research, Department of Defense Translational Team Science Award W81XWH-17-1-0491; NCI SPORE P50 CA127003; the Gallagher Chair in Gastrointestinal Cancer Research and the Target Cancer Foundation; and the MGH Award of Excellence.
About the National Center for the Advancement of Translational Sciences (NCATS): NCATS conducts and supports research into the science and workings of translation – the process by which interventions to improve health are developed and implemented – to enable more treatments to reach more patients, faster. For more information on how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.
About the National Institutes of Health (NIH):The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.
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