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The process of making proteins, the complex molecules that do most of the jobs required for life, can go awry at any stage, and turn a normal cell into a cancerous one.
Christina Termini, a cancer cell biologist who joined Fred Hutch Cancer Center in 2022, has won a $600,000, three-year award from the V Foundation for Cancer Research to study how a late stage of that process affects treatment for the deadliest blood cancer, acute myeloid leukemia, or AML.
Her project focuses on what happens after the genetic instructions for making proteins have been translated into sequences of amino acids, when the proteins acquire some add-ons before reporting for duty.
Those add-ons — a garland of fats tacked on here, a ribbon of sugars attached there — can significantly modify how the protein interacts with other molecules.
“The function of a molecule can be completely different depending on whether it has certain structures attached to it or not,” Termini said. “That’s what’s gotten me jazzed as a scientist for a long time.”
A process that adorns sugar ribbons with sulfate "sparkles" to enhance binding with other molecules goes wrong in AML, which has a 5-year overall survival rate of approximately 30%.
That dysregulation may shield some tumor cells from the effects of chemotherapy, enabling them to survive undetected and eventually cause relapse, which occurs in about 30% of AML patients within three years of diagnosis.
The leading cause of death of adult AML patients is relapse, which is particularly cruel because it occurs after a period of remission following treatment when AML is no longer detectable and appears to be defeated.
Figuring out what shields some tumors from chemotherapy
Founded in 1993 by ESPN and the late North Carolina State University basketball coach Jim Valvano, the V Foundation for Cancer Research requires institutions to nominate the strongest applicant chosen from an internal competition for the award.
Termini, an assistant professor in the Translational Science and Therapeutics and Human Biology divisions, was Fred Hutch’s unanimous choice.
“She is an exceptional early-career scientist specializing in blood cancers with an aptitude for rigorous research and innovative discoveries,” said Fred Hutch director and holder of the Raisbeck Endowed Chair, Thomas J. Lynch Jr., MD, in his nominating letter.
During her academic training, Termini studied how fats modify proteins after translation.
“Now I’m more of a sugar person, thinking about how those slight changes can lead to major consequences in the cell,” said Termini.
Her winning proposal builds on thesis work by Kelsey Woodruff, a PhD candidate in her lab who is in the Molecular and Cellular Biology Graduate Program at the University of Washington.
Sum of sparkles greater than its parts
Termini will focus on a process called heparan sulfation, which happens after genetic sequences are translated. Heparan sulfation dots the proteins’ sugar ribbons with sparkles called sulfates.
Sulfation modifies the function of proteins on the cell’s surface: The negatively charged sulfate sparkles make it easier to snag a wide variety of positively charged molecules floating around outside the cell.
Binding to sparkles enables molecules to transmit information about the surrounding environment and initiate signaling within the cell that triggers various functions essential for survival.
Some sparkles bind to molecules that promote cell growth; others bind to molecules that inhibit growth.
In AML, depleting one kind of sparkle in experiments is correlated with more tumor growth.
Another sparkle is over-produced in AML tumor cells and is associated with worse outcomes for patients. Depleting that kind of sparkle is correlated with more tumor cell death from chemotherapy.
Termini hopes to establish with experiments which sparkles in which combinations make some cells more resistant to chemotherapy than others.
“There’s a code of sparkles,” Termini said. “Not just one sparkle of a given kind causes a specific function, but the sum of them. This is why we are working to dissect how they function one sparkle at a time, and eventually, we will look at them together.”
Making sense of that sparkle code may open new therapeutic possibilities to curb tumor growth and shatter the shield protecting tumor cells from chemotherapy.
“In order to curb relapse, we need to understand how we can better target leukemia cells,” she said.
