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Effective targeting of RNA polymerase I in treatment-resistant prostate cancer.
Prostate 2019P

Abstract

BACKGROUND

Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation.

METHODS

The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models.

RESULTS

We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Ptenfl/fl (BMPC) mouse prostate cancer model.

CONCLUSION

Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.

Authors+Show Affiliations

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.Department of Pathology, Urology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Pathology, Urology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland.Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31524299

Citation

Low, Jin-Yih, et al. "Effective Targeting of RNA Polymerase I in Treatment-resistant Prostate Cancer." The Prostate, 2019.
Low JY, Sirajuddin P, Moubarek M, et al. Effective targeting of RNA polymerase I in treatment-resistant prostate cancer. Prostate. 2019.
Low, J. Y., Sirajuddin, P., Moubarek, M., Agarwal, S., Rege, A., Guner, G., ... Laiho, M. (2019). Effective targeting of RNA polymerase I in treatment-resistant prostate cancer. The Prostate, doi:10.1002/pros.23909.
Low JY, et al. Effective Targeting of RNA Polymerase I in Treatment-resistant Prostate Cancer. Prostate. 2019 Sep 16; PubMed PMID: 31524299.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effective targeting of RNA polymerase I in treatment-resistant prostate cancer. AU - Low,Jin-Yih, AU - Sirajuddin,Paul, AU - Moubarek,Michael, AU - Agarwal,Shreya, AU - Rege,Apurv, AU - Guner,Gunes, AU - Liu,Hester, AU - Yang,Zhiming, AU - De Marzo,Angelo M, AU - Bieberich,Charles, AU - Laiho,Marikki, Y1 - 2019/09/16/ PY - 2019/06/25/received PY - 2019/08/30/accepted PY - 2019/9/17/entrez KW - RNA polymerase I KW - androgen receptor KW - ribosome biogenesis KW - small molecule KW - therapeutics KW - transcription JF - The Prostate JO - Prostate N2 - BACKGROUND: Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation. METHODS: The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models. RESULTS: We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Ptenfl/fl (BMPC) mouse prostate cancer model. CONCLUSION: Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer. SN - 1097-0045 UR - https://www.unboundmedicine.com/medline/citation/31524299/Effective_targeting_of_RNA_polymerase_I_in_treatment_resistant_prostate_cancer_ L2 - https://doi.org/10.1002/pros.23909 DB - PRIME DP - Unbound Medicine ER -