Small-molecule RNA therapeutics to target prostate cancer

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

Small-molecule RNA therapeutics to target prostate cancer

Duygu Kuzuoglu-Ozturk et al. Cancer Cell. 2025.

. 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.

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Conflict of interest statement

Declaration of interests S.T.W. is a founder, shareholder, and former CEO of eFFECTOR Therapeutics, Inc. D.R. is a shareholder of eFFECTOR Therapeutics, Inc., and a member of its scientific advisory board.

References

1. Cancer Facts & Figures 2024 | American Cancer Society; https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts....
1. Buccitelli C, and Selbach M (2020). mRNAs, proteins and the emerging principles of gene expression control. Nat. Rev. Genet. 21, 630–644. 10.1038/s41576-020-0258-4. - DOI - PubMed
1. Kovalski JR, Kuzuoglu-Ozturk D, and Ruggero D (2022). Protein synthesis control in cancer: selectivity and therapeutic targeting. EMBO J. 41, e109823. 10.15252/embj.2021109823. - DOI - PMC - PubMed
1. Rubio CA, Weisburd B, Holderfield M, Arias C, Fang E, DeRisi JL, and Fanidi A (2014). Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 15, 476. 10.1186/s13059-014-0476-1. - DOI - PMC - PubMed
1. Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, Van der Meulen J, et al. (2014). RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70. 10.1038/nature13485. - DOI - PMC - PubMed

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Small-molecule RNA therapeutics to target prostate cancer

Affiliations

Small-molecule RNA therapeutics to target prostate cancer

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Miscellaneous