Researchers at the University of Michigan Rogel Cancer Center have uncovered a key mechanism that may explain why some prostate tumors become more aggressive and resistant to treatment.
Led by Dr. Joshi Alumkal, the team identified a protein, lysine-specific demethylase 1 (LSD1), as a critical driver of this transformation.
Their findings also suggest that drugs targeting LSD1 could offer new hope for patients with hard-to-treat prostate cancers.
The Problem: Lineage Plasticity in Prostate Cancer
Most prostate tumors, known as adenocarcinomas, respond well to initial treatments.
However, a subset undergoes a process called lineage plasticity, changing into a more aggressive form known as neuroendocrine prostate cancer. This transformation significantly limits treatment options and worsens patient outcomes.
LSD1’s Role in Cancer Progression
LSD1 plays a key role in regulating gene activity in both healthy and cancerous cells. Previous research by the team revealed that LSD1 helps adenocarcinoma tumors survive by activating stem cell-related genes.
In this study, the researchers found that LSD1 is even more active in neuroendocrine prostate cancers than in adenocarcinomas.
When they removed LSD1 from neuroendocrine cancer cells, tumor growth was dramatically reduced. Interestingly, blocking LSD1’s ability to interact with other proteins proved more effective than simply inhibiting its enzymatic activity.
Dr. Anbarasu Kumaraswamy and the team tested a class of drugs called allosteric inhibitors that block LSD1’s interactions with other proteins. Among these drugs, seclidemstat—currently in phase 1 clinical trials for sarcoma—showed exceptional promise.
In preclinical studies using mice, seclidemstat not only halted tumor growth but also caused some tumors to regress entirely, with no observed toxicity. This makes it a strong candidate for further testing in prostate cancer.
LSD1 and p53: A Key Connection
The research also uncovered that LSD1 deactivates p53, a critical tumor-suppressing gene. When LSD1 was inhibited, p53 became reactivated, leading to reduced tumor growth.
This suggests that reactivating p53 is an essential component of LSD1-targeting therapies and could potentially benefit other cancers where p53 is inactivated.
These findings highlight the potential of LSD1 inhibitors, like seclidemstat, to treat aggressive prostate cancers.
Given that seclidemstat is already being tested in clinical trials for another type of cancer, researchers are optimistic about its rapid development for neuroendocrine prostate cancer.
Moreover, the discovery that LSD1 inhibition can reactivate p53 suggests that this approach might be extended to other cancers, broadening its therapeutic impact.
This breakthrough represents a significant step toward new treatments for aggressive prostate cancer and possibly other challenging cancers.
By targeting the mechanisms that drive tumor progression, researchers are opening doors to therapies that could improve survival and quality of life for many patients.
The study was published in JCI Insight.
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