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Like many young scientists in the last five years, postdoctoral researcher Yeon Soo Kim, PhD, has struggled to launch a career during turbulent times.
She joined Fred Hutch Cancer Center during the COVID-19 pandemic, working with prostate cancer expert and medical oncologist Andrew C. Hsieh, MD, who holds the Larry and Virginia Gordon Endowed Chair in Prostate and Bladder Cancer Research.
Her discoveries about a key component of RNA that regulates how cells make proteins, the complex molecules that do the cell’s work, led to her application for a prestigious five-year grant from the National Institutes of Health that recognizes researchers likely to become leaders in their field.
But just as normalcy appeared to return with the end of the pandemic, a new obstacle arose as her NIH application stalled for months amid efforts to radically change how the U.S. government funds scientific research.
“I applied last year, but their advisory committee meeting, which is supposed to be held in February, got cancelled like everyone else's,” Kim said.
The meeting was rescheduled for June and then, after more than a year of waiting, she got the good news.
She received a K99/R00 Pathway to Independence Award from the National Cancer Institute, a branch of the NIH, beginning July 1.
The award funds one to two years of mentored research at Fred Hutch as much as $125,000 each year (the K99 part). If she secures a tenure-track or equivalent faculty position, she will receive up to three years of research funding at $249,000 per year (the R00 part).
“She proposes a unique angle in tackling the problem of cancer, focusing on the RNA components of the translation apparatus,” Hsieh said. “Her current work is very exciting, and I think it will make a big splash in our field.”
How depletion of a key RNA molecule helps prostate cancer evade drugs
Kim began her postdoctoral research in the Hsieh Lab at Fred Hutch in 2021 after earning her PhD at Pennsylvania State University’s College of Medicine.
“I moved to Seattle to join Andrew's lab during COVID, which was a difficult time,” Kim said.
She had studied ovarian cancer at Penn State but found a new direction in Seattle.
“I decided to switch to a prostate cancer when I joined Andrew's lab because I was more interested in the mechanistic insights of how cancer cells grow and resist therapies rather than the type of cancer per se,” Kim said. “I was drawn to Andrew’s research because he is a really well-known expert in protein synthesis control in cancer.”
Last year, Hsieh won a $1 million grant, in collaboration with a researcher at the Institute of Cancer Research in London, from the Prostate Cancer Foundation to find new therapies for drug-resistant prostate cancer.
Kim’s NIH project builds on research she has already accomplished in Hsieh’s lab, which focuses on the last stages of the hormonal supply chain that tumors need to grow.
Advanced prostate cancer, which has spread beyond the prostate to other parts of the body, resists treatment with surgery as well as drugs that interrupt a vital hormonal supply chain tumors need to grow.
When treatments block the flow of testosterone, the cancer inevitably finds molecular workarounds that re-establish the supply chain, triggering more runaway tumor growth that hastens death.
Those workarounds often occur in the last links of that supply chain — when genetic instructions copied by messenger RNA get translated into amino acids to make the actual proteins fueling tumor growth.
Kim’s research focused on another type of RNA that plays an important role in building proteins called transfer RNA, which brings the right amino acids at the right time during protein synthesis.
Kim discovered a significant reduction in a transfer RNA called Arg-TCT in an aggressive subtype of prostate cancer.
Her experiments across a wide variety of specimens revealed that when the level of that key transfer RNA drops, the cells no longer respond to drugs aimed at stopping the flow of testosterone.
‘Dr. Kim is a dedicated scientist who has both the brains and inner drive to succeed.’
— Fred Hutch physician-scientist Dr. Andrew Hsieh
She will use some of her NIH award to figure out the complex mechanism of how that works, which could lead to more effective treatments for advanced prostate cancer.
Exploring the understudied staging area for protein construction
Kim will also use her grant to explore a stretch of DNA that gets copied in messenger RNA but isn’t usually translated into amino acids to build a protein.
It comes right before the sequence containing the code for making a protein and acts like a staging area at a construction site.
“That’s where all the protein machinery builds up to start translation,” she said.
The staging area includes several elements that regulate the preparation and stability of messenger RNA as well as the initiation of translation.
Cancer exploits mutations in the staging area to find workarounds that evade therapies, but it has not been studied as much because the DNA region isn’t translated along with the actual code for making proteins.
Kim will study this region in prostate, bladder, lung and breast cancers, using CRISPR gene-editing techniques to knock out different elements of the staging area and measure what effect their absence has on whether the cancer cell thrives or dies.
“What we are trying to do is to characterize this area of interest that is very deleterious to cells and then hopefully find some targets that we can block and help advance therapeutic interventions against these cancers in the future,” she said.
She already has a good idea of where to look.
She used CRISPR to systematically target and disrupt the staging area region of genes known to be involved in prostate cancer. She then treated those cells with a common drug used to treat prostate cancer called enzalutamide.
The experiment revealed that disruptions to the staging area of several genes combined with the drug killed cancer cells more effectively than either the knockouts or the drug acting alone.
That suggests that something in the staging area helps cancer compensate when it’s exposed to the drug, but if those elements are knocked out, the cancer can’t find a workaround to become drug-resistant.
“If we target that area, knock it out with a CRISPR screen, or hopefully in the future characterize this area and maybe develop a drug, then we could reduce therapeutic resistance in prostate cancer,” Kim said. “That’s the whole idea.”
Federal Funding Helps Us Save Lives
At Fred Hutch, 70% of our research funding comes from federal grants, which are awarded based on scientific merit. This level of federal funding is a direct reflection of our proven ability to make landmark breakthroughs and our trusted ability to lead large scientific collaborations.
NIH mission includes training next generation
The NIH traditionally has played a significant role in training the next generation of scientists, a commitment exemplified by the Pathway to Independence Award (K99/R00) for postdoctoral scientists who show promise as future leaders in the field.
“It's a very competitive award and I’m so grateful to have received it,” Kim said.
She has begun the mentored phase of the award in Hsieh’s lab. Her other mentors include Michael Haffner, MD, PhD, and Alice Berger, PhD, at Fred Hutch, Gabriele Varani, PhD, at the University of Washington and Tao Pan, PhD, at the University of Chicago.
“Hopefully, I can develop my project further in the Hsieh lab and one day soon I can have my own lab launched in the next few years,” Kim said.