Researchers from the University of Michigan Rogel Cancer Center have discovered a new mechanism that may explain the transformation of some prostate tumors from a commonly treatable form to a more aggressive and rarer version. The team, led by Joshi Alumkal, M.D., Wicha Family Professor of Oncology, focused on the protein lysine-specific demethylase 1 (LSD1), which plays a pivotal role in regulating genes in both normal and cancer cells and is notably active in certain aggressive prostate cancers. By targeting LSD1, the team believes there's potential to counter the resistance seen in these aggressive forms.
Most prostate tumors retain their original glandular structure after receiving treatments that lower male hormones. However, a subset undergoes a shift known as lineage plasticity, where the tumor adopts a nerve or brain-like constitution. This shift results in limited treatment options.
“Aggressive forms of prostate cancer are on the rise as a work-around to some of our newer, more potent hormonal treatments,” Alumkal commented. “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 identities, including one called neuroendocrine prostate cancer.”
This neuroendocrine form of prostate cancer results in poorer patient outcomes, and treatment options remain limited. Alumkal's lab is committed to understanding this transition and finding ways to counteract it.
The team's research into LSD1 showed its higher expression in neuroendocrine prostate tumors compared to adenocarcinoma tumors. By deactivating LSD1 in neuroendocrine prostate cancer cells through RNA interference, the team observed that these cancer models were less viable, underscoring the protein's role in the survival of these aggressive cells.
Another key finding was LSD1's ability to deactivate p53, a gene that typically acts to suppress tumor growth. When LSD1 was inhibited, p53 activity resumed, suppressing tumor growth. Anbarasu Kumaraswamy, Ph.D., a member of the Alumkal Laboratory, mentioned that a specific class of drugs known as allosteric inhibitors was particularly effective in inhibiting LSD1 and curtailing cancer cell growth.
In experiments involving mice implanted with neuroendocrine prostate tumors, the team found that the drug seclidemstat, currently in phase 1 clinical trials for sarcoma, effectively halted tumor growth. Alumkal expressed optimism about the potential benefits of LSD1 inhibitors for treating aggressive prostate cancers, emphasizing the importance of developing clinical trials targeting this protein. He also noted that these findings could offer strategies to reignite p53 function in other cancers.
Read the original publication here.
Most prostate tumors retain their original glandular structure after receiving treatments that lower male hormones. However, a subset undergoes a shift known as lineage plasticity, where the tumor adopts a nerve or brain-like constitution. This shift results in limited treatment options.
“Aggressive forms of prostate cancer are on the rise as a work-around to some of our newer, more potent hormonal treatments,” Alumkal commented. “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 identities, including one called neuroendocrine prostate cancer.”
This neuroendocrine form of prostate cancer results in poorer patient outcomes, and treatment options remain limited. Alumkal's lab is committed to understanding this transition and finding ways to counteract it.
The team's research into LSD1 showed its higher expression in neuroendocrine prostate tumors compared to adenocarcinoma tumors. By deactivating LSD1 in neuroendocrine prostate cancer cells through RNA interference, the team observed that these cancer models were less viable, underscoring the protein's role in the survival of these aggressive cells.
Another key finding was LSD1's ability to deactivate p53, a gene that typically acts to suppress tumor growth. When LSD1 was inhibited, p53 activity resumed, suppressing tumor growth. Anbarasu Kumaraswamy, Ph.D., a member of the Alumkal Laboratory, mentioned that a specific class of drugs known as allosteric inhibitors was particularly effective in inhibiting LSD1 and curtailing cancer cell growth.
In experiments involving mice implanted with neuroendocrine prostate tumors, the team found that the drug seclidemstat, currently in phase 1 clinical trials for sarcoma, effectively halted tumor growth. Alumkal expressed optimism about the potential benefits of LSD1 inhibitors for treating aggressive prostate cancers, emphasizing the importance of developing clinical trials targeting this protein. He also noted that these findings could offer strategies to reignite p53 function in other cancers.
Read the original publication here.