Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor variant 7 (AR-V7) is a key driver in castration-resistant prostate cancer (CRPC) progression.
• AR-V7 lacks a ligand-binding domain, conferring resistance to hormonal therapies and leading to poor patient outcomes.
• Current therapeutic options targeting AR-V7 are limited.

Purpose of the Study:

• To investigate the efficacy of novel agents, thailanstatins (TSTs) and spliceostatin A analogs, against AR-V7.
• To elucidate the molecular mechanism by which these agents suppress AR-V7 expression.
• To evaluate the in vivo anti-tumor activity of these agents in CRPC models.

Main Methods:

• Treatment of CRPC cells with thailanstatins and spliceostatin A analogs.
• Assessment of AR-V7 mRNA and protein expression levels.
• Investigation of the interaction between U2AF65 and SAP155 in AR-V7 splicing.
• Evaluation of TST-D efficacy in human CRPC xenograft models.

Main Results:

• TSTs significantly suppressed AR-V7 mRNA and protein expression, with a lesser effect on full-length AR.
• TST-D inhibited AR-V7 gene splicing by disrupting the U2AF65-SAP155 interaction at the polypyrimidine tract.
• TST-D demonstrated potent tumor inhibition and induced apoptosis in CRPC xenografts.

Conclusions:

• The machinery regulating AR gene splicing in CRPC represents a viable drug target.
• Thailanstatins are a novel class of anti-AR-V agents with significant potential for clinical development.
• TSTs show promise as a new therapeutic strategy for CRPC patients resistant to current therapies.