LIN28B Promotes the Development of Neuroendocrine Prostate Cancer
This week we profile a recent publication in the Journal of Clinical Investigation
from the laboratory of Dr. Xuesen Dong (pictured) at UBC.
Can you provide a brief overview of your lab’s current research focus?
Our research focuses on understanding the mechanisms by which prostate tumours develop therapy resistance. Obtained information from these studies will then direct us to design diagnostics and therapeutics for prostate cancer patients. We believe that the androgen receptor (AR) remains to be the driver in the majority of prostate adenocarcinoma, however, inhibitors targeting the AR protein itself are not sufficient to fully block AR activity. Co-targeting AR cofactors such as DNA topoisomerase II is an alternative therapeutic option. We are designing new catalytic topoisomerase II inhibitors to target the AR signaling in prostate cancer cells.
Since more potent AR inhibitors are available to treat prostate cancer patients, therapy-induced neuroendocrine prostate cancer with low or no AR activity is becoming more prevalent and is expected to be a major therapeutic challenge in the near future. We are investigating how the stem-like gene network regulates cancer cell plasticity and promotes the development of neuroendocrine prostate tumours. Compelling evidence showed that Lin28b plays an important role in regulating the lineage switch of prostatic luminal epithelial cells to neuroendocrine cells. We are designing small molecules to target Lin28b activity and test them in our in house cell models.
What is the significance of the findings in this publication?
This study identified a potential therapeutic target to treat therapy-induced neuroendocrine prostate cancer, a lethal subtype of therapy-resistant prostate cancers. This information will direct future strategies to design new therapeutics to treat this type of tumour.
What are the next steps for this research?
We are applying a rational drug design pipeline to target Lin28b and inhibit its RNA processing capacity. There are a few candidate compounds that are being tested in the neuroendocrine prostate cancer cell and xenograft models.
This work was funded by:
These works are supported by the CIHR, DoD Prostate Cancer Award.