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The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer
Clinical cancer research, 2016-11, Vol.22 (22), p.5539-5552
Rebello, Richard J
Kusnadi, Eric
Cameron, Donald P
Pearson, Helen B
Lesmana, Analia
Devlin, Jennifer R
Drygin, Denis
Clark, Ashlee K
Porter, Laura
Pedersen, John
Sandhu, Shahneen
Risbridger, Gail P
Pearson, Richard B
Hannan, Ross D
Furic, Luc
2016
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Rebello, Richard J
Kusnadi, Eric
Cameron, Donald P
Pearson, Helen B
Lesmana, Analia
Devlin, Jennifer R
Drygin, Denis
Clark, Ashlee K
Porter, Laura
Pedersen, John
Sandhu, Shahneen
Risbridger, Gail P
Pearson, Richard B
Hannan, Ross D
Furic, Luc
Titel
The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer
Ist Teil von
Clinical cancer research, 2016-11, Vol.22 (22), p.5539-5552
Ort / Verlag
United States
Erscheinungsjahr
2016
Quelle
MEDLINE
Beschreibungen/Notizen
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. 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. 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. 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.
Sprache
Englisch
Identifikatoren
ISSN: 1078-0432
eISSN: 1557-3265
DOI: 10.1158/1078-0432.ccr-16-0124
Titel-ID: cdi_proquest_miscellaneous_1846420278
Format
–
Schlagworte
Animals
,
Antineoplastic Agents - pharmacology
,
Azepines - pharmacology
,
Benzothiazoles - pharmacology
,
Cell Cycle Checkpoints - drug effects
,
Cell Line, Tumor
,
Cell Proliferation - drug effects
,
Female
,
Humans
,
Indoles - pharmacology
,
Male
,
Mice
,
Naphthyridines - pharmacology
,
Prostate - drug effects
,
Prostate - metabolism
,
Prostatic Neoplasms - drug therapy
,
Prostatic Neoplasms - metabolism
,
Protein Kinase Inhibitors - pharmacology
,
Proto-Oncogene Proteins c-myc - metabolism
,
Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors
,
PTEN Phosphohydrolase - metabolism
,
RNA Polymerase I - antagonists & inhibitors
,
Signal Transduction - drug effects
,
Transcription, Genetic - drug effects
,
Xenograft Model Antitumor Assays - methods
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