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Clin Cancer Res. 2016 Nov 15;22(22):5539-5552. doi: 10.1158/1078-0432.CCR-16-0124. Epub 2016 Aug 2.

The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer.

Author information

1
Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia.
2
Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
3
Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
4
Pimera, Inc. San Diego, California.
5
TissuPath Pathology, Melbourne, Victoria, Australia.
6
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
7
Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. luc.furic@monash.edu ross.hannan@anu.edu.au rick.pearson@petermac.org.
8
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
9
Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
10
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
11
Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia. luc.furic@monash.edu ross.hannan@anu.edu.au rick.pearson@petermac.org.

Abstract

PURPOSE:

The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.

EXPERIMENTAL DESIGN:

The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.

RESULTS:

CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.

CONCLUSIONS:

Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res; 22(22); 5539-52. ©2016 AACR.

PMID:
27486174
DOI:
10.1158/1078-0432.CCR-16-0124
[Indexed for MEDLINE]
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