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.
The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models.
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.
Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.
The Prostate. 2019 Sep 16 [Epub ahead of print]
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
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 Pathology, Urology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.