Effective targeting of RNA polymerase I in treatment-resistant prostate cancer

Jin Yih Low; Paul Sirajuddin; Michael Moubarek; Shreya Agarwal; Apurv Rege; Gunes Guner; Hester Liu; Zhiming Yang; Angelo M. De Marzo; Charles Bieberich; Marikki Laiho

doi:10.1002/pros.23909

Effective targeting of RNA polymerase I in treatment-resistant prostate cancer

Jin Yih Low, Paul Sirajuddin, Michael Moubarek, Shreya Agarwal, Apurv Rege, Gunes Guner, Hester Liu, Zhiming Yang, Angelo M. De Marzo, Charles Bieberich, Marikki Laiho

School of Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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|Pten^fl/fl (BMPC) mouse prostate cancer model. Conclusion: Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.

Original language	English (US)
Pages (from-to)	1837-1851
Number of pages	15
Journal	Prostate
Volume	79
Issue number	16
DOIs	https://doi.org/10.1002/pros.23909
State	Published - Dec 1 2019

Keywords

RNA polymerase I
androgen receptor
ribosome biogenesis
small molecule
therapeutics
transcription

ASJC Scopus subject areas

Oncology
Urology

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10.1002/pros.23909

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@article{a9999d501863428890849310ebaf691e,

title = "Effective targeting of RNA polymerase I in treatment-resistant prostate cancer",

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.",

keywords = "RNA polymerase I, androgen receptor, ribosome biogenesis, small molecule, therapeutics, transcription",

author = "Low, {Jin Yih} and Paul Sirajuddin and Michael Moubarek and Shreya Agarwal and Apurv Rege and Gunes Guner and Hester Liu and Zhiming Yang and {De Marzo}, {Angelo M.} and Charles Bieberich and Marikki Laiho",

note = "Funding Information: This study was supported by the Prostate Cancer Foundation 2014 Safeway Foundation-PCF Challenge Award, NIH P30 CA006973 (to ML and AMDM), NIH/NCI Prostate SPORE P50CA058236, Harrington Discovery Institute, and Patrick C. Walsh Prostate Cancer Research Fund. Funding Information: This study was supported by the Prostate Cancer Foundation 2014 Safeway Foundation‐PCF Challenge Award, NIH P30 CA006973 (to ML and AMDM), NIH/NCI Prostate SPORE P50CA058236, Harrington Discovery Institute, and Patrick C. Walsh Prostate Cancer Research Fund. Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",

year = "2019",

month = dec,

day = "1",

doi = "10.1002/pros.23909",

language = "English (US)",

volume = "79",

pages = "1837--1851",

journal = "Prostate",

issn = "0270-4137",

publisher = "Wiley-Liss Inc.",

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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

N1 - Funding Information: This study was supported by the Prostate Cancer Foundation 2014 Safeway Foundation-PCF Challenge Award, NIH P30 CA006973 (to ML and AMDM), NIH/NCI Prostate SPORE P50CA058236, Harrington Discovery Institute, and Patrick C. Walsh Prostate Cancer Research Fund. Funding Information: This study was supported by the Prostate Cancer Foundation 2014 Safeway Foundation‐PCF Challenge Award, NIH P30 CA006973 (to ML and AMDM), NIH/NCI Prostate SPORE P50CA058236, Harrington Discovery Institute, and Patrick C. Walsh Prostate Cancer Research Fund. Publisher Copyright: © 2019 Wiley Periodicals, Inc.

PY - 2019/12/1

Y1 - 2019/12/1

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.

AB - 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.

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KW - androgen receptor

KW - ribosome biogenesis

KW - small molecule

KW - therapeutics

KW - transcription

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JO - Prostate

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ER -

Effective targeting of RNA polymerase I in treatment-resistant prostate cancer

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Keywords

ASJC Scopus subject areas

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