Promising new approach targets aggressive type of prostate cancer
Researchers have uncovered the molecular mechanism that drives an aggressive form of prostate cancer that doesn’t respond well to typical treatments. Importantly, they also identified a drug currently undergoing clinical trials that can potentially treat it.
Adenocarcinoma, or glandular prostate cancer, is the most common type of prostate cancer. One first-line treatment for advanced prostate cancer is hormone therapy to block the effects of androgen in the body, which can help prevent prostate cancer cells from growing. However, for some men, treatment can cause the cancer to morph into a more aggressive form called neuroendocrine prostate cancer (NEPC), the most lethal prostate cancer there is and one that has no definitive treatment.
In a new study, researchers from Michigan Medicine at the University of Michigan expanded on their previous work, which identified a key driver of cell growth in prostate cancer, and discovered the pathway that leads to the development of NEPC. More importantly, they identified a way to treat it.
The process by which adenocarcinomas shift to NEPC is known as lineage plasticity, a kind of cellular reprogramming where cells transition from one committed pathway to another as a means of bypassing therapy. The mechanisms driving lineage plasticity are not well understood, but what is known is that once it occurs, few treatment options exist.
“Our prior work demonstrated that approximately 15-20% of patients whose tumors start growing despite newer hormonal treatments will lose the adenocarcinoma program and take on other identifies, including one called neuroendocrine prostate cancer,” said Joshi Alumkal, corresponding author of the study.
That prior work identified that the protein lysine-specific demethylase 1 (LSD1) was important for the survival of prostate adenocarcinoma tumors. In the current study, the researchers wanted to see whether LSD1 was also involved in NEPC.
Examination of tissues from patients with metastatic prostate cancer showed that LSD1 was more highly expressed in NEPC tumors than in adenocarcinoma tumors. To determine the importance of LSD1, the researchers removed LSD1 from cell models of NEPC and found that the cells grew less well, demonstrating that LSD1 was essential for the survival of these aggressive cells.
They then tested whether blocking the interaction of LSD1 with other proteins could inhibit its actions.
“Ultimately, we found that a class of drugs – allosteric inhibitors – that block protein-protein interactions was much more effective in stopping LSD1 and slowing the growth of cancer cells,” said Anbarasu Kumaraswamy, the study’s lead author.
Figuring out how LSD1 works led the researchers to identify key genes and molecular pathways controlled by LSD1 in NEPC. They discovered that LSD1 turned off the gene TP53, which provides instructions for making a tumor-suppressing protein, p53. If LSD1 was inhibited in cancer cell models, p53 was reactivated and tumor growth was suppressed.
“That cell lines lacking p53 were less sensitive to LSD1 inhibition gives us strong clues about the importance of p53 reactivation for the anti-tumor effects of LSD1 inhibition,” said Alumkal.
The next step was to test the effectiveness of a known LSD1 inhibitor. The researchers used mouse models to test the effectiveness of seclidemstat, a drug that’s currently undergoing phase 1 clinical trials as a treatment for sarcoma, a cancer that starts in the bones and connective tissue. In every case, the drug blocked NEPC tumor growth and in several tumors there was complete regression.
The researchers say their findings suggest a potential treatment for patients with NEPC and other cancers.
“The fact that the drug we found is in clinical testing gives us hope that we might be able to develop clinical trials targeting LSD1 in aggressive prostate cancers in the near term,” Alumkal said. “These findings could also lead to a more generalizable approach to reactivating p53 function in other cancers.”
The study was published in the journal JCI Insight.