Small-molecule RNA therapeutics to target prostate cancer

Duygu Kuzuoglu-Ozturk; Hao G Nguyen; Lingru Xue; Emma Figueredo; Vishvak Subramanyam; Isabelle Liu; Kenya Bonitto; Ashish Noronha; Adrianna Dabrowska; Janet E Cowan; Juan A Oses-Prieto; Alma L Burlingame; Stephen T Worland; Peter R Carroll; Davide Ruggero

doi:10.1016/j.ccell.2025.02.027

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. Epub 2025 Mar 20.

Authors

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
PMCID: PMC12124822 (available on 2026-05-12)
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.

MeSH terms

5' Untranslated Regions
Animals
Cell Line, Tumor
Eukaryotic Initiation Factor-4A / antagonists & inhibitors
Eukaryotic Initiation Factor-4A / genetics
Eukaryotic Initiation Factor-4A / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Mice
Prostatic Neoplasms* / genetics
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / pathology
RNA, Messenger / chemistry
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Thiohydantoins* / pharmacology
Xenograft Model Antitumor Assays

Substances

Receptors, Androgen
Hypoxia-Inducible Factor 1, alpha Subunit
Eukaryotic Initiation Factor-4A
Thiohydantoins
AR protein, human
5' Untranslated Regions
HIF1A protein, human
RNA, Messenger

Abstract

MeSH terms

Substances

Grants and funding