Researchers at the University of Michigan have discovered a powerful new way to stop prostate cancer from growing—by targeting the genetic “switches” that fuel tumor development.
Their findings could pave the way for a new class of treatments for men with advanced prostate cancer that no longer responds to standard hormone therapy.
The study, published in Nature Genetics, was led by Dr. Arul Chinnaiyan, director of the Michigan Center for Translational Pathology.
His team focused on a special chemical tag called H2B N-terminal acetylation (H2BNTac), which acts as a signal to activate genes that drive cancer growth.
These tags are added by two proteins known as p300 and CBP, working together with the androgen receptor—a key molecule that promotes prostate cancer cell survival.
The researchers discovered that prostate cancer tissues have much higher levels of H2BNTac, p300, and CBP compared to normal prostate cells.
These molecules help turn on “enhancers,” sections of DNA that control the activity of cancer-promoting genes. In essence, they act like a gas pedal that speeds up tumor growth.
To stop this process, the Michigan team collaborated with Dr. Shaomeng Wang, a medicinal chemistry expert, to design a new drug called CBPD-409.
This compound selectively destroys both p300 and CBP, removing the H2BNTac mark and shutting down the androgen receptor’s ability to activate tumor genes. CBPD-409 is highly potent and can be taken orally, making it a promising candidate for future clinical use.
“When we degraded p300 and CBP, we saw that the H2BNTac marks disappeared from enhancer sites,” said Dr. Chinnaiyan.
“This means we could essentially erase the signals that prostate cancer uses to keep growing. CBPD-409 works much more effectively than earlier drugs, which only partially blocked these proteins.”
In laboratory tests, prostate cancer cells with higher levels of H2BNTac were more sensitive to the new drug, suggesting it could be particularly effective for certain patients. In mouse models of advanced, treatment-resistant prostate cancer, CBPD-409 not only slowed tumor growth but also caused significant tumor shrinkage—all while being well tolerated.
Earlier drugs that targeted p300 and CBP showed limited success because they didn’t completely shut down the proteins’ function. The new compound overcomes this problem by degrading them entirely, representing what the researchers call a “next-generation” approach.
“This study reveals the unique power of targeted protein degradation,” said Chinnaiyan. “By removing the proteins completely, we can stop prostate cancer at one of its core control points.”
Dr. Wang added that these findings could lead to a new therapy for castration-resistant prostate cancer, an aggressive form that no longer responds to hormone treatments. “Our results strongly support moving this drug forward for clinical testing,” he said.
Prostate cancer remains the most common cancer among men in the United States and one of the leading causes of cancer-related deaths. This breakthrough offers new hope for developing treatments that directly target the disease’s molecular machinery.
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Source: University of Michigan.
