One major challenge in developing new therapies to treat cancer is figuring out how normal cells and cancer cells differ, so that treatment has fewer side effects.
Now a molecular biologist at the University of Texas Southwestern Medical Center is pursuing an enzyme, boosted in some cancers, that he thinks might provide an Achilles heel to attack them.
Vincent Tagliabracci was recruited in 2015 from the University of California, San Diego, where he was a postdoctoral fellow, to the UT Southwestern Department of Molecular Biology.
Tagliabracci focuses on a family of enzymes, called kinases, involved in cell signaling. The essential function of kinases has been understood for some time—they transfer a phosphate group from an energy molecule, called ATP, to another biomolecule, turning it on. These enzymes are often mutated in cancers and have received intense scrutiny for many decades.
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One major challenge in developing new therapies to treat cancer is figuring out how normal cells and cancer cells differ, so that treatment has fewer side effects.
Now a molecular biologist at the University of Texas Southwestern Medical Center is pursuing an enzyme, boosted in some cancers, that he thinks might provide an Achilles heel to attack them.
Vincent Tagliabracci was recruited in 2015 from the University of California, San Diego, where he was a postdoctoral fellow, to the UT Southwestern Department of Molecular Biology.
Tagliabracci focuses on a family of enzymes, called kinases, involved in cell signaling. The essential function of kinases has been understood for some time—they transfer a phosphate group from an energy molecule, called ATP, to another biomolecule, turning it on. These enzymes are often mutated in cancers and have received intense scrutiny for many decades.
The enzyme he studies is one that is ramped up in certain cancers, like breast and pancreatic. To his surprise, when Tagliabracci studied the crystal structure of the kinase he isolated, he found the ATP molecule flipped 180 degrees. He discovered that this kinase keeps the phosphate molecule and transfers the other part of the parent molecule, AMP, to other proteins. He called this process “AMPylation.”
The significance of AMPylation, he says, is that it regulates proteins involved in responding to oxidative stress. Any time a cell utilizes energy, it generates reactive oxygen that if not tamped down would damage DNA, proteins, and lipids.
Cancer cells have a bevy of anti-oxidant enzymes that protect them from reactive oxygen species. If Tagliabracci can figure out how to prevent the anti-oxidant enzymes from being activated, perhaps cancer cells would self-destruct, or at least become more sensitive to other forms of chemotherapy.
“We’re trying to develop a very specific inhibitor, because it’s so very different from all of the other kinases,” he says, “which is very important for reducing some of the off-target effects.” He plans to use UT Southwestern’s high-throughput screening core facility to find drug candidates.
He says UT Southwestern is an institution with great support for junior faculty, and that CPRIT support allowed him to do curiosity-driven research. “CPRIT is an amazing tool to attract some of the best and brightest researchers from all over the world to Texas,” he says. “Some of the discoveries may not be immediately transferred to the clinic but they certainly will in the long run.”
And CPRIT’s investment in Tagliabracci has paid off not only in terms of discoveries but also in the follow-on funding he’s received: a $2.3 million New Innovator Award from the National Institutes of Health and a further $300,000 Searle Scholars Award.
Tagliabracci received his undergraduate degrees in chemistry and biology from the University of Indianapolis, and his Ph.D. in biochemistry & molecular biology from Indiana University. He began his postdoctoral fellowship at UCSD in 2010.
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