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Read more about Fred Hutch achievements and accolades.
The Damon Runyon Cancer Research Foundation recently awarded two Fred Hutch Cancer Center postdoctoral fellows grants to support investigations of leukemia and lung infections in cancer patients. Vivian Liu, MD, received a Damon Runyon Physician-Scientist Training Award and Sahana Kuthyar, PhD, was named a Damon Runyon Quantitative Biology Fellow. Their translationally focused work will help improve cancer treatment and supportive care.
Untangling AML subtypes for better treatments
Liu studies acute myeloid leukemia and the biological and genetic processes that drive this cancer. Her four-year, $460,000 Damon Runyon Physician-Scientist Award will support her efforts to better understand how a mutation found in about 30% of adult AML cases drives cancer and could potentially be targeted therapeutically.
“This award is nice for me in particular, because it’s for MDs that want to pursue translational research, which is not the most common pathway,” said Liu, who is co-mentored by Fred Hutch leukemia biologists Stanley Lee, PhD and Soheil Meshinchi, MD, PhD. “It will allow me to spend more time dedicated to my lab training.”
She focuses on a subgroup of AML that has mutations in a gene called NPM1. The NPM1 protein is usually found in the cell nucleus (which houses its DNA), but AML-associated mutations change where it goes within the cell and how it functions.
“Initially we thought mutant NPM1 was mostly localizing to the cytoplasm [outside the nucleus] … but more recently folks have also found that it has a role in altering chromatin [DNA packaging] and transcription,” Liu said.
She has found that NPM1-mutated AML has a different genetic signature than other subtypes of AML. Liu is exploring how changes in NPM1 localization and function, including its ability to regulate how genes are turned on and off, give rise to this signature and could drive AML.
While bone marrow transplant remains the gold standard of AML treatment, not everyone can undergo transplant. New therapies called menin inhibitors have recently been approved to treat relapsed or refractory NPM1-mutated AML and AML with alterations in a different gene, KMT2A. While menin inhibitors can induce remissions, most patients still develop resistance to menin inhibitors and relapse.
Liu will work to understand how these two varieties of AML differ biologically and in their responses to menin inhibitors. She hopes her findings will help improve patients’ treatment options. Historically, there have been few successes in the search for targeted AML treatments, she said.
Liu’s work could aid in “finding either combinations that can prolong [the time to relapse] or eradicate relapse entirely, or finding better targets that will work for more patients and for longer,” she said. “Because not everyone can get transplanted, finding combinations that could be given to even more people, with fewer side effects, is really important for the disease.”
Teasing out cancer patients’ immune vulnerabilities
Kuthyar’s three-year, $240,000 Damon Runyon Quantitative Biology Fellowship will support her investigations of how cancer treatments and even supportive care can make cancer patients more vulnerable to serious lung infections like pneumonia.
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While treatments like chemotherapy and radiation fight a patient’s cancer, “they also weaken key parts of the immune system that normally help detect and eliminate bacteria,” said Kuthyar, who is co-mentored by Fred Hutch cancer pulmonologist Jared Mayers, MD, PhD, and Fred Hutch biostatistician Michael Wu, PhD.
This immunosuppression makes cancer patients much more vulnerable to lung infections, and their visits to clinics and hospitals also raise their risk of exposure. On top of this, many cancer patients hospitalized for lung infections receive supplemental oxygen — which can also alter the lung environment in ways that help bacteria grow, Kuthyar said.
“These two factors are connected in cancer patients because we know that the weakened immune system can’t effectively deal with bacteria and the high oxygen environment promotes bacterial survival and virulence,” she said.
Not every cancer patient on supplemental oxygen will get a severe lung infection, but to get a better sense of who's most at risk — and how to intervene — Kuthyar needs to dig into the interplay between lung microenvironment, immune system and bacteria.
“We’re going to need this two-punch effect in which we figure out why this is happening and what is the mechanism behind it, and how can therapies capture that mechanism and turn it against itself,” she said.
Kuthyar will be using an “exciting trifecta” of model systems, including data from a large patient cohort of cancer patients who have received supplemental oxygen, an immunosuppressed mouse model and an in vitro lab dish-based system.
The patient cohort will allow her to assess different factors, including metabolites, bacterial traits and immune factors, which could contribute to whether cancer patients contract lung infections. Using these data, Kuthyar will develop various hypotheses she can then test in mice and cell culture.
“It’s a very computationally intensive grant,” she said. “I’ll be using a lot of network modeling to link the metabolomics and metatranscriptomic data from bacteria with our human immunological profiling data.”
Building out the in vitro system to test her hypotheses, and validating them in her models, will take time, Kuthyar said.
“I am really thankful this award will give me the time and funding to do that,” she said. “And importantly, I’m not a traditionally trained cancer biologist, so I’m thankful for this chance to step into that world and learn from other Damon Runyon fellows.”
