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Two researchers at Fred Hutch Cancer Center recently received Young Investigator Awards from the Prostate Cancer Foundation for their work investigating epigenetic features of aggressive prostate cancer that could lead to more personalized care and better results from existing therapies.
Epigenetics focuses on DNA modifications that do not change the underlying sequence.
Every cell of the human body has the same set of genes encoded in DNA, but when cells specialize into different tissues, they only need a subset of those genes turned on.
A second “epigenetic” code customizes DNA with chemical tags that regulate which genes are turned on and off in specific circumstances, such as when a generic cell in early development becomes a muscle, skin, kidney or brain cell.
Some epigenetic changes drive cancer, but those changes can be manipulated without changing the underlying genetics, making them a promising target for therapy.
Pallabi Mustafi, PhD, a postdoctoral researcher in the lab of Michael Haffner, MD, PhD, received a Young Investigator Award for research into a subtype of aggressive prostate cancer she discovered. The subtype is characterized by an unusual epigenetic modification that responds well to a combination of drugs.
Ruben Raychaudhuri, MD, PhD, also received a Young Investigator Award to test an epigenetic approach that could make a recently approved therapy more effective in aggressive prostate cancer by increasing the contrast between tumor cells and normal tissue.
The awards provide $75,000 a year for three years and include collaboration with mentors. Haffner is a mentor for both recipients.
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Discovery of a new subtype of aggressive prostate cancer
After earning her PhD in India, Mustafi joined the Haffner Lab in the Human Biology Division at Fred Hutch in 2022 as a postdoctoral researcher.
Haffner’s lab is interested in DNA methylation, an epigenetic modification that typically happens early in the development of a growing organism when generic cells turn into brain, bone, skin and muscle cells and no longer need access to all the genes in the cell’s DNA.
DNA methylation chemically tags the unnecessary genes, which masks them from the processes that copy genetic instructions for how to make all the cell’s essential molecular workers.
“I came to Michael's lab because he had this DNA methylation project he wanted somebody to lead,” Mustafi said. “I had an epigenetics background, and I have a huge interest in epigenetics.”
Often in cancer, more “hyper” DNA methylation occurs at specific sites in some genes, but Mustafi discovered a subset of prostate cancer tumors that had the opposite problem. Instead of hyper DNA methylation, these tumors have very low methylation globally across the genome.
“I identified certain tumors that just lose this modification on a very large scale, so that got us interested in how these tumors are different,” she said. “This is a very important mark and generally cells try to maintain it. We got fascinated with how the cells are tolerating such loss and yet acting like a tumor.”
The tumors with low or “hypo” DNA methylation are so different and distinct from healthy tissue it’s easy to identify them. Mustafi found that about 30% of the samples she studied had this distinct signature that is particularly aggressive and linked to poor outcomes for patients.
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Further investigation revealed that tumors with this signature can be targeted with a drug directly combined with a second drug that prevents cancer from finding an escape hatch.
She will use her Young Investigator Award to define the biology of this subtype and provide the preclinical foundation for potential new therapies.
“Dr. Mustafi’s project is highly innovative and has strong potential to benefit patients,” Haffner said. “She has discovered that certain prostate cancers with specific epigenetic changes are especially sensitive to a combination of drugs that are already being tested in clinical trials.”
Her research shows that relatively simple molecular tests can identify which patients are most likely to benefit.
“When given to the right patients, this drug combination appears to be very effective,” Haffner said. “This research not only improves our understanding of how these cancers behave but also has the potential to change how we treat men with advanced prostate cancer by better matching therapies to the patients most likely to respond.”
Though her focus is on prostate cancer, she has found a similar pattern of “low” DNA methylation across many different tumor types, including bladder and skin tumors.
“Most of my studies also show that this is something which can have a broader implication across different tumor types if we can understand the biology,” she said.
Using epigenetic changes to make an existing therapy better
Prostate specific membrane antigens (PSMA) are useful molecules for diagnosis and therapy because they are dramatically overproduced in aggressive cancer and easy to find on the surface of cells, like beacons that provide sharp contrast between tumors and normal tissue.
A recently approved radiotherapy attacks aggressive prostate cancer by homing in on PSMA. But only 50% of patients respond to this therapy, in part, because PSMA levels in some tumor cells are too low.
Raychaudhuri, a faculty member in the Clinical Research Division at Fred Hutch, and his colleagues have discovered that blocking one of the DNA methylation enzymes with a drug can boost levels of PSMA, making the cell more visible to the radiotherapy that targets them.
“Dr. Raychaudhuri is developing a new approach to “prime” cancer cells using epigenetic therapy so that they produce more PSMA, making them easier to target,” Haffner said. “This strategy builds on strong laboratory research and represents an important step toward improving how well these treatments work in patients.”
In addition to Haffner, Raychaudhuri is also mentored by Michael Schweizer, MD, and Peter Nelson, MD, who holds the Stuart and Molly Sloan Precision Oncology Institute Endowed Chair.
Raychaudhuri’s project involves a “proof-of-concept” clinical trial to assess the safety and efficacy of this approach.
