Open Collections

Ho, Chia Hao

University of British Columbia

The use of next-generation anti-androgens in the treatment of prostate cancer has led to an increase in therapy-induced neuroendocrine prostate cancer (t-NEPC). Recent studies have identified t-NEPC as a highly aggressive subtype of prostate cancer with poor survival rates. Our laboratory has recently demonstrated that the Lin28B, a core embryonic protein that suppresses the maturation process of the micro-RNA let-7, plays a crucial role in transforming adenocarcinoma prostate cancer (AdPC) into t-NEPC. Lin28B is an RNA-binding protein with two critical domains: the cold-shock domain (CSD) and the zinc-knuckle domain (ZKD). By utilizing both of CSD and ZKD domains, Lin28B protein can structurally binds to the microRNA let-7, which has been reported as a tumor suppressor and oncogene in NEPC, and inhibits its biosynthesis. Therefore, we hypothesize that blocking the interaction of CSD or ZKD with let-7 using a small molecule chemical may provide therapeutic opportunities to treat t-NEPC. In this study, we used a computer-aided drug design strategy to target Lin28B ZKD with small molecule inhibitors. We identified several inhibitors that effectively block Lin28B from binding to let-7 miRNA and restore let-7 biogenesis. Furthermore, we demonstrated that these inhibitors suppress the expression of stem-like pluripotency gene networks and neuroendocrine biomarkers. Lin28B inhibitors also reduces the expression of cancer stem cell surface markers such as CD44 and CD133. We also showed that these inhibitors suppress t-NEPC cell proliferation and clonogenic abilities. Overall, our study discovered several promising small molecules inhibitors of Lin28B that could be developed into potential drugs against NEPC.

Text

2023-10-12

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86124

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/