2. Academic Validation
  3. Small-molecule RNA therapeutics to target prostate cancer

Small-molecule RNA therapeutics to target prostate cancer

  • Cancer Cell. 2025 May 12;43(5):841-855.e8. doi: 10.1016/j.ccell.2025.02.027.
Duygu Kuzuoglu-Ozturk 1,  Hao G Nguyen 2,  Lingru Xue 3,  Emma Figueredo 3,  Vishvak Subramanyam 4,  Isabelle Liu 4,  Kenya Bonitto 5,  Ashish Noronha 3,  Adrianna Dabrowska 3,  Janet E Cowan 3,  Juan A Oses-Prieto 6,  Alma L Burlingame 6,  Stephen T Worland 7,  Peter R Carroll 3,  Davide Ruggero 8
Affiliations

Affiliations

  • 1 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
  • 2 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address: hao.nguyen@ucsf.edu.
  • 3 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 4 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • 5 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Tetrad Graduate Program, University of California, San Francisco, CA, USA.
  • 6 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 7 eFFECTOR Therapeutics, San Diego, USA.
  • 8 Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: davide.ruggero@ucsf.edu.
PMID: 40118049 DOI: 10.1016/j.ccell.2025.02.027
Abstract

Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for Cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate Cancer, castration-resistant prostate Cancer (CRPC), we use a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eukaryotic initiation factor 4A (eIF4A). Zotatifin represses tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis reveals two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential Cancer modulator in hypoxia. We solve the structure of the 5' UTRs of these oncogenic mRNAs and strikingly observe complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.

Keywords

5′ UTR; AR; HIF1A; RNA structure; combinational therapy; eIF4A; mCRPC; prostate cancer; translational control; zotatifin.

Figures
Products