Small-molecule RNA therapeutics to target prostate cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeting protein expression via RNA structure modulation is an emerging therapeutic strategy.
• Castration-resistant prostate cancer (CRPC) remains a lethal malignancy with limited treatment options.

Purpose of the Study:

• To investigate the therapeutic potential of targeting RNA structure in CRPC using the small molecule zotatifin.
• To identify key oncogenic targets regulated by zotatifin in CRPC.

Main Methods:

• Utilized zotatifin, a small molecule inhibitor of eukaryotic initiation factor 4A (eIF4A).
• Performed genome-wide transcriptome, translatome, and proteomic analyses.
• Determined the 5' UTR structures of key oncogenic mRNAs.
• Evaluated zotatifin efficacy in patient-derived and xenograft CRPC models.

Main Results:

• Zotatifin repressed tumorigenesis and prolonged survival in vivo when combined with hormone therapy.
• Identified androgen receptor (AR) and hypoxia-inducible factor 1A (HIF1A) as critical translational targets of zotatifin.
• Observed significant structural remodeling of AR and HIF1A mRNAs by zotatifin.
• Zotatifin treatment sensitized tumors to anti-androgen therapy and radiotherapy.

Conclusions:

• Zotatifin demonstrates therapeutic efficacy in CRPC models by targeting AR and HIF1A mRNA translation.
• "Translatome therapy" represents a promising strategy for treating advanced cancers.
• Combined therapeutic approaches enhance treatment sensitivity in CRPC.