Targeting RNA Polymerase I Transcription Activity in Osteosarcoma: Pre-Clinical Molecular and Animal Treatment Studies
Chang-Won Kang,
Anneke C. Blackburn,
Amos Hong Pheng Loh,
Kuick Chick Hong,
Jian Yuan Goh,
Nadine Hein,
Denis Drygin,
Chris R. Parish,
Ross D. Hannan,
Katherine M. Hannan,
Lucy A. Coupland
Affiliations
Chang-Won Kang
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Anneke C. Blackburn
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Amos Hong Pheng Loh
VIVA-KKH Paediatric Brain and Solid Tumour Programme, Children’s Blood and Cancer Centre, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Kuick Chick Hong
Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Jian Yuan Goh
Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Nadine Hein
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Denis Drygin
Regulus Therapeutics, 4224 Campus Point C, San Diego, CA 92121, USA
Chris R. Parish
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Ross D. Hannan
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Katherine M. Hannan
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Lucy A. Coupland
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
The survival rate of patients with osteosarcoma (OS) has not improved over the last 30 years. Mutations in the genes TP53, RB1 and c-Myc frequently occur in OS and enhance RNA Polymerase I (Pol I) activity, thus supporting uncontrolled cancer cell proliferation. We therefore hypothesised that Pol I inhibition may be an effective therapeutic strategy for this aggressive cancer. The Pol I inhibitor CX-5461 has demonstrated therapeutic efficacy in different cancers in pre-clinical and phase I clinical trials; thus, the effects were determined on ten human OS cell lines. Following characterisation using genome profiling and Western blotting, RNA Pol I activity, cell proliferation and cell cycle progression were evaluated in vitro, and the growth of TP53 wild-type and mutant tumours was measured in a murine allograft model and in two human xenograft OS models. CX-5461 treatment resulted in reduced ribosomal DNA (rDNA) transcription and Growth 2 (G2)-phase cell cycle arrest in all OS cell lines. Additionally, tumour growth in all allograft and xenograft OS models was effectively suppressed without apparent toxicity. Our study demonstrates the efficacy of Pol I inhibition against OS with varying genetic alterations. This study provides pre-clinical evidence to support this novel therapeutic approach in OS.
