Prostate cancers are generally treatable with positive survival outcomes. However, following common treatments such as androgen receptor inhibitors, some prostate tumours undergo cellular reprogramming, transitioning into aggressive tumours that are much more difficult to treat. A recent study published in JCI Insight sheds light on a key protein involved in this process known as LSD1, which could be targeted to treat this aggressive tumour type.
Lineage plasticity
At diagnosis, almost all prostate cancers are adenocarcinomas driven by androgen receptor signalling. These tumours are generally receptive to hormone therapies targeting the androgen receptor. Following this treatment however, some tumours undergo cellular reprogramming with neuronal differentiation, known as linage plasticity, to become an aggressive and difficult to treat subset. It is currently unknown why this happens, however this neuroendocrine prostate cancer (NEPC) is resistant to androgen therapy and has much worse survival outcomes.
Cases of aggressive NPEC are becoming increasingly common due to the widespread use of androgen therapies in prostate cancer treatment. However, there are currently no effective treatments available for NEPC.
A target protein
Researchers at the University of Michigan Rogel Cancer Centre have made a breakthrough in pinpointing a protein responsible for this cellular lineage switch. The group had previously identified lysine-specific demethylase 1 (LSD1) as a key driver promoting androgen receptor-independent survival of prostate adenocarcinoma cells, by promoting stemness and survival. Building on this work, researchers now have found that LSD1 is highly upregulated in NEPC compared to adenocarcinoma tumours, and so may have a role in this change.
In this study, RNAseq analysis found that LSD1 suppresses the TP53 tumour suppressor pathway, making cells vulnerable to malignant transformation. The researchers tested different anti-LSD1 drug treatments on NEPC cells and found that allosteric (protein) inhibitors were more effective than catalytic inhibitors at reducing cell survival. These drugs work by disrupting the LSD1-HDAC interaction and increasing histone acetylation at TP53 targets (Figure 1). LSD1 inhibition reactivates the TP53 pathway and restarts TP53 signalling, which is critical for the anti-tumour effects of LSD1 inhibition. Testing this further in mouse models, researchers showed that LSD1 inhibition can successfully suppress NEPC tumour growth in vivo.
Figure 1. LSD1 inhibitors disrupt the LSD1-HDAC interaction in NEPC cells, increasing histone acetylation at TP53 targets and reducing cell survival. Taken from Kumaraswamy et al. 2023.
An exciting prospect
These findings suggest that blocking LSD1’s function may be a promising treatment strategy for NEPC. One of the drugs that was effective in mouse models was seclidemstat, an anti-LSD1 drug, which is currently in phase I clinical trials for use in sarcoma. It is hoped that this drug may also have applications in not only prostate cancer, but other cancer types too.
“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,” says Joshi Alumkal, M.D., Wicha Family Professor of Oncology, and leader of the genitourinary medical oncology section at Rogel. “These findings could also lead to a more generalizable approach to reactivating p53 function in other cancers.”
