title: The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rebello
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Kusnadi
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.|Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Cameron
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Analia
authors.initials: A
authors.lastname: Lesmana
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Devlin
authors.affiliation: Pimera, Inc. San Diego, California.
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Ashlee K
authors.initials: AK
authors.lastname: Clark
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Porter
authors.affiliation: TissuPath Pathology, Melbourne, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shahneen
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Cancer Program, Biomedicine Discovery Institute and Department of Anatomy & Developmental Biology, Monash University, Victoria, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: 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.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: 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.|Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia.|School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: 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.
authors.forename: Luc
authors.initials: L
authors.lastname: Furic
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D052160:Benzothiazoles; C557717:CX 5461; C000607921:CX-6258; D007211:Indoles; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D012318:RNA Polymerase I; D051059:PTEN Phosphohydrolase