Fred Hutch Cancer Center and Kugel Lab postdoctoral fellow Stephanie Dobersch, PhD, received an American Cancer Society Fellowship to study a highly lethal form of pancreatic cancer, known as basal pancreatic ductal adenocarcinoma (PDA). Dobersch’s two-year, $146,000 ACS Fellowship will enable her to understand how a unique genetic program drives basal PDA and discover the subtype’s potential therapeutic vulnerabilities.
“Patients with basal PDA need targeted therapies, so it’s important to study this subtype,” Dobersch said.
She hopes her findings will help change the treatment landscape for pancreatic cancer patients, who still face grim prognoses and a limited array of therapies.
ACS Fellowships support postdoctoral fellows as they broaden their research experience in preparation for independent careers in cancer research. Dobersch credited her Fred Hutch mentor and pancreatic cancer expert Sita Kugel, PhD, with helping her expand her scientific repertoire and polish her grant- and manuscript-writing skills.
“Sita is an exceptional mentor whose guidance has been invaluable to my scientific journey,” Dobersch said. “She is an inspiring woman in science.”
Kugel, in turn, touted Dobersch’s careful experimentation, deeply considered approach and fearless pursuit of new techniques and hypotheses.
“Stephanie has been a wonderful addition to my lab,” Kugel said. “She helps to elevate all the science in the lab. I am so proud of all she has accomplished and look forward to the meaningful impact she will undoubtably have on understanding the biology of pancreatic cancer.”
Most pancreatic cancers are PDAs. These arise from exocrine cells, which form enzyme-producing glands in the pancreas. PDAs are more aggressive and lethal than the slower-growing neuroendocrine tumors that arise from insulin-producing endocrine cells.
ACS estimates that in 2024, over 66,000 people will be diagnosed with pancreatic cancer in the US, and that nearly 52,000 people will die from the disease. Overall, people diagnosed with pancreatic cancer are only 13% as likely to live five more years as those without it.
A patient’s prognosis can vary depending on what “flavor” of PDA they have. About 30% of patients with PDA have the basal type that Dobersch will study, while 70% have what’s known as the “classical” type. Each is defined by a signature mix of genes that help the tumor form, survive and progress. Basal-type PDAs tend to be more aggressive than classical-type PDAs and have been harder to study because of their relative rarity.
This disparity in research attention is already creating a disparity in access to potential new, targeted treatments. There are new therapies on the horizon that target cells with cancer-promoting mutations in a gene, called KRAS, which is mutated in PDA. (One such drug has been approved by the U.S. Food and Drug Administration for non-small cell lung cancer.) But while classical PDAs still depend on this mutation, and may be susceptible to these new drugs, basal PDAs no longer rely on these mutations to survive.
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Researchers need to discover the weaknesses lurking within the unique molecular makeup of basal PDAs. Kugel had previously found that basal PDAs turn on genes that are usually expressed only in early embryonic development. In particular, she found a couple of key genes that influence chromatin, the complex of DNA and protein that facilitates DNA compaction and helps regulate gene expression.
Switching these genes back on helps basal PDA cells survive and spread — but the genes could also make these tumors vulnerable. Surprisingly, the chromatin changes in these cells influence protein synthesis as well: basal PDAs make proteins at a much higher level than normal.
“They’re ‘addicted’ to this high level of protein synthesis,” Dobersch said.
This could mean that hobbling the tumors’ ability to produce proteins could also hamper their growth and survival. Dobersch aims to find out.
“Our goal is to understand the mechanism in a little more detail,” she said. “We want to know how these tumors depend on the high protein synthesis and how to manipulate the signaling pathway in order to specifically kill these tumor cells.”
In addition to getting a better general understanding of basal PDA biology, Dobersch will also screen FDA-approved drugs for other diseases that can put the brakes on high protein production. The fact that these drugs have already made it through the approval process will help fast-track any that show promise against pancreatic cancer.
“We need to take bigger steps toward new treatment options,” Dobserch said.
Kugel’s work has been made possible through support from the V Foundation as well as other public and private funders, including Swim Across America.
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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