Prostate cancer is a common cancer in men. While it often grows slowly, some forms can become aggressive and spread. Treating advanced prostate cancer is challenging because cancer cells can become resistant to therapies.
Researchers have found a promising new way to slow down treatment-resistant prostate cancer. They are targeting two important cancer pathways at the same time.
Understanding Prostate Cancer and Resistance
About one in eight men will be diagnosed with prostate cancer in their lifetime. Many survive, but for some, the cancer spreads and becomes metastatic. In the U.S., it's the second leading cause of cancer-related death among men.
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Start Your News DetoxMost prostate tumors act like gland tissue and rely on male hormones called androgens, like testosterone, to grow. Because of this, androgen receptor inhibitors are the main treatment for metastatic prostate cancer. These drugs often work at first, but almost all patients eventually become resistant.
How Tumors Change Identity
Some resistant tumors find ways around treatment. They activate different pathways that change their cellular makeup. This makes the cancer cells lose their gland-like features and take on new identities. This change is called transdifferentiation.
University of Michigan researchers published their findings in JCI Insight. They identified two pathways that can be targeted together in prostate tumors that have undergone transdifferentiation.
This strategy might also help with other cancers that change identity, such as lung and pancreatic cancers. Earlier research showed that losing the TP53 and RB1 genes is linked to transdifferentiation in prostate cancer. However, the exact reason for this link was not clear.
Targeting Two Pathways for Better Control
To understand this process, researchers studied several prostate cancer cell lines. They wanted to see which cellular pathways changed when TP53 and RB1 genes were missing.
Joshi Alumkal, M.D., a professor at Rogel Cancer Center, explained that this transition has two parts. First, glandular genes are lost. Second, cell programs activate, causing the cells to switch to stem cell-like identities.
Previous work by these researchers showed that drugs called BET bromodomain inhibitors can disrupt pathways that allow prostate cancer cells to activate these new identity programs. However, these drugs did not permanently stop the disease.
In the current study, BET bromodomain inhibitors again slowed prostate cancer cell growth but did not kill the cells. The researchers then looked at DNA methyltransferase (DNMT) inhibitors. These drugs can turn back on genes, including glandular genes, that are often switched off when prostate cancers change identity. DNMT inhibitors are already approved by the FDA for other conditions, like blood cancers.
Improved Results with Combination Therapy
When researchers combined BET bromodomain inhibitors with DNMT inhibitors, prostate cancer cell growth was suppressed more effectively than with either drug alone. This combination also showed similar results in tumors grown in mice.
Will Storck, Ph.D., a research lab specialist in the Alumkal lab, noted that using both drugs reversed many of the gene expression changes in the tumors. He added that the combination significantly reduced tumor growth even at much lower doses and was well tolerated by the mice.
Future Directions and Hope
The researchers now want to find out which specific genes are responsible for these anti-tumor effects. They also want to identify biomarkers that could help predict which patients would benefit most from this drug combination.
Another goal is to learn if transdifferentiation can be stopped before the cell transformation begins. Dr. Alumkal believes preventing transdifferentiation would be crucial for patient survival. Identifying patients whose tumors might undergo this change could help use this treatment effectively and earlier.
The team hopes to start clinical trials to see if this drug combination works in patients with transdifferentiated prostate cancer. They also plan to investigate if targeting both pathways could help treat other cancers that undergo similar changes.
Deep Dive & References
Combined BET bromodomain and DNMT inhibition targets critical survival pathways in transdifferentiated prostate cancer - JCI Insight, 2026
