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Three Fred Hutch Cancer Center scientists were recently awarded research grants from the American Cancer Society (ACS). The awards will fund projects examining how mutations in cell metabolism can lead to different types of cancer in different tissue types, how a class of drugs that inhibit cellular transcription may be used to target a rare form of liver cancer, and how a protein that normally helps restrain cancer cell growth is regulated in certain liver cancer cells.
Lucas Sullivan, PhD, associate professor in the Human Biology Division, received an ACS Discovery Boost grant for his project “Understanding Tissue Specificity of Metabolic Mutations in Cancer.” Sita Kugel, PhD, professor in the Human Biology Division and holder of the Leung Roy Family Endowed Chair, received an ACS Mission Boost Stage I grant for her project “Targeting lineage plasticity in intrahepatic cholangiocarcinoma.” Liberalis “Debraj” Boila, PhD, a postdoctoral researcher in the Kugel Lab, received an ACS postdoctoral fellowship for his project “Mechanistic Dissection and Pharmacologic Reactivation of PP2A in IDH1-Mutant Intrahepatic Cholangiocarcinoma.”
The American Cancer Society, the largest private nonprofit entity funding cancer research in the United States, supports projects at all stages of the research pipeline, from initial high-risk high-reward concepts to full clinical trials.
Why some cancers occur in some tissues, but not others
Sullivan will use his two-year grant of $297,000 to delve into a cellular mystery: Why do some types of mutations cause cancer in some tissues, but not in others? His project will examine mutations in the mitochondria: the “powerhouse” organelles inside cells that manufacture the bulk of an organism’s adenosine triphosphate (ATP) using a set of chemical reactions known as the Krebs cycle.
ATP provides the energy for all living cells to function, and mutations in the enzymes that regulate the Krebs cycle can break the cycle, causing intermediate molecules to accumulate inside the cell instead of moving through the Krebs cycle normally. These “oncometabolites” are so named because they are products of the cell’s metabolic pathways and they can cause cancer by interfering with the cell’s ability to regulate normal cell functions. The mystery is that different oncometabolites cause different cancers in different parts of the body.
“[Oncometabolites] are all structurally very similar,” Sullivan said. “They all interfere with epigenetics [the process by which genes are either expressed or repressed in a cell]. They, to varying degrees, interfere in similar signaling processes. But the strange thing about it is that they cause different cancers.”
As one example, the enzyme fumarate hydratase (FH) breaks down fumarate, one of the products of the Krebs cycle, when it is functioning normally. A loss-of-function mutation in the FH gene leads to an abnormally high concentration of fumarate inside the cell. This can trick some kidney cells into changing their behavior and turning the cell cancerous.
A different mutation in the Krebs cycle, in the gene for isocitrate dehydrogenase (IDH), leads to a different Krebs cycle malfunction: the accumulation of a molecule not normally found in human cells, 2-hydroxyglutarate (2-HG), which interferes with proper gene expression by causing too much of a process called methylation. This interference keeps cells from maturing properly, causing cells in some parts of the body (such as the blood, where it can cause leukemia) to flood with immature, nonfunctional cells. But while IDH mutations are often observed in leukemia and can also be seen in liver cancer, this mutation isn’t seen in kidney cancer.
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Sullivan will use in vitro experiments (laboratory experiments conducted with cell lines in test tubes) to examine how certain types of cells that are already predisposed to form cancer will either become cancerous or die depending on the type of Krebs cycle mutation introduced into the cell.
“There is a pre-leukemia cell line called TF1 that, if you give it an IDH mutation, it will show changes consistent with developing into leukemia,” Sullivan explained. “Let’s take those cells and give them an IDH mutation. But let’s also give them, in a different test tube, an SDH [succinate dehydrogenase] or FH mutation. Do they similarly transform into cancer cells?”
Sullivan expects that pre-leukemic cells with non-leukemia metabolic mutations will not transform, because SDH and FH mutations are not observed in leukemia. The question is, why?
“It’s possible that there is a difference in the metabolic tolerance of these mutations, where a pre-leukemia cell can tolerate an IDH2 mutation because of the metabolic downsides of it are not very severe [in that cell], but an FH or an SDH mutation is too deleterious to get the oncogenic upside,” leading to cell death instead of growth promotion seen in cancer, Sullivan said.
Sullivan’s hope is that by identifying specific qualities associated with the metabolic changes in a cell that becomes cancerous versus one that does not, that future studies could identify specific targets for therapy depending on the type of mutation seen in a cell and by learning how it promotes disease.
A scientific legacy reaps new benefits in cholangiocarcinoma research
Kugel’s grant will provide $297,000 over two years for a project examining intrahepatic cholangiocarcinoma (ICC), a rare form of primary liver cancer that begins in the bile ducts within the liver itself.
The project is a testament both to Kugel’s previous research studying pancreatic cancer, and to a scientific legacy that had its start in her late husband’s lab at Fred Hutch, which focused on ICC.
Kugel’s initial discovery found that a class of drugs that block a cell’s ability to provide the instructions needed to make new cells was effective in an aggressive subtype of pancreatic cancer. When comparing to ICC, a form of liver cancer that is often discovered late and can be particularly difficult to treat effectively, she found many similarities in the phenotypes [the observable characteristics] of the ICC and pancreatic cancer cells, causing her to question whether some of the cells’ vulnerabilities could be similar as well. She has since identified the subtype of ICC that is sensitive to this same class of therapeutics.
Kugel’s grant will support a project identifying subtypes of ICC that lack a specific hepatobiliary differentiation protein. The ICC cells lacking this protein rely heavily on the machinery that provides instructions for making new proteins in order to survive. By blocking a protein called CDK7 with a drug that kept it from encouraging the cell to transcribe protein-making instructions, the cancer cells’ growth was arrested and the cells died instead of multiplying.
Kugel explained that if this approach proves successful, it could create the opportunity to treat biomarker-deficient cells with a highly specific drug that could target only those cells that were dividing rapidly, leading to a new approach in precision medicine for the treatment of an otherwise difficult-to-treat condition.
These are not the only exciting findings from Kugel’s lab that could lead to new treatments for ICC.
“We found a master regulator of one of the cholangiocarcinoma cell states,” she said. “And that is going to be a biomarker for the patients that can either respond or not respond to this drug.”
The ACS Mission Boost Stage I grant provides support for preclinical proof-of-concept research with a potential for therapeutic value in cancer treatment. Kugel’s aim is to gather data from preclinical models to qualify for Stage II grants, which fund the clinical trial itself.
“By linking tumor biology to therapeutic response, our goal is to expand precision medicine approaches and offer hope to patients with limited options,” she said.
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A molecular ‘glue’ for a cancer-suppressing protein
Kugel was one of two ACS awardees in her lab. Boila, a postdoctoral researcher in the Kugel Lab, received a two-year ACS Postdoctoral Fellowship. He will study a different aspect of ICC: how a specific protein acts in the presence of an IDH mutation found in between 10% and 20% of patients with this disease. (A third lab member, postdoctoral fellow Stephanie Dobersch, PhD, received a two-year ACS fellowship in 2024 to study pancreatic cancer.)
“I’m super proud of him,” Kugel said of Boila. “This is a really important stepping stone in his career. I’m so grateful to ACS for their support, and I’m really excited to see where the research goes.”
Boila’s project will look at how a protein known as protein phosphatase 2A (PP2A) acts in ICC cells with a specific mutation in the isocitrate dehydrogenase (IDH) gene known as IDH1. The project will examine how the protein, a “trimeric” protein with three specific subunits, can be held together to stay functional using a combination of treatments that includes small molecules that act as a “glue” to keep the protein functioning normally when mutant IDH1 could otherwise render it inactive.
PP2A is a phosphatase — a type of enzyme that removes phosphate groups from proteins. This action can turn off the activity of a protein. PP2A can act as a “brake” on cancer growth when it is functioning normally, Boila explained. But PP2A activity can be influenced by two chemical modifications: the addition of a phosphate group, which can inhibit its function, or a methyl group, which can promote its activity. Whether the PP2A is functional or not depends on the balance between those two chemical reactions, a process that is not yet well understood.
“This project asks how that function is regulated, and whether restoring the activity of that brake can make treatment more effective,” he said. “So we are combining studies of the underlying biology of PP2A with treatment experiments in lab models.”
In previous work, Boila, Kugel and others showed that inhibiting a protein known as SRC (pronounced “sark”) in IDH-mutant ICC enabled the formation of a protein complex that included PP2A along with another protein, MAGI1. This combined MAGI1-PP2A complex led to reduced cell growth in these cancer cells. Boila’s current project will examine PP2A from several angles, including combining a mutant IDH1 inhibitor with a molecular “glue” developed by collaborator Goutham Narla, MD, PhD, at the University of Michigan.
Ultimately, Boila said, he wants to understand the mechanism of IDH1-mutant ICC more thoroughly in order to find more effective ways to treat the disease.
Boila’s fellowship is a testament to his perseverance as well as his science, as he had applied multiple times for this honor before finally receiving it this year.
“This was my final resubmission,” he said. “The fellowship has gotten very competitive over the years. From my first submission to when I finally got the award, I think the proposal and the science behind it has become so much better. Over the years of working with Sita, I’ve realized that you just have to keep persevering, and that is something that I intend to take with me and keep at the back of my mind as I progress.”
Boila hopes to pursue an independent research career after the completion of his postdoctoral fellowship.
“I definitely want to stay in academia and continue working with cholangiocarcinoma, which has now become my passion, and take the science forward,” he said. “I hope I can make a difference.”
