TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model
Brice Moukengue,
Hannah K Brown,
Céline Charrier,
Séverine Battaglia,
Marc Baud'huin,
Thibaut Quillard,
Therese M Pham,
Ioannis S Pateras,
Vassilis G Gorgoulis,
Thomas Helleday,
Dominique Heymann,
Ulrika Warpman Berglund,
Benjamin Ory,
Francois Lamoureux
Affiliations
Brice Moukengue
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
Hannah K Brown
Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK; University of Sheffield, INSERM, European Associated Laboratory “Sarcoma Research Unit”, Medical School, S10 2RX, Sheffield, UK
Céline Charrier
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
Séverine Battaglia
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
Marc Baud'huin
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France; CHU de Nantes, Nantes, France
Thibaut Quillard
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
Therese M Pham
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
Ioannis S Pateras
Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece
Vassilis G Gorgoulis
Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Centre, The University of Manchester, Manchester, UK
Thomas Helleday
Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
Dominique Heymann
Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK; University of Sheffield, INSERM, European Associated Laboratory “Sarcoma Research Unit”, Medical School, S10 2RX, Sheffield, UK; INSERM, U1232, CRCINA, Institut de Cancérologie de l'Ouest, University of Nantes, Université d'Angers, Blvd Jacques Monod, 44805 Saint-Herblain, France
Ulrika Warpman Berglund
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
Benjamin Ory
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France
Francois Lamoureux
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France; Correspondence to: INSERM UMR1238 – PhyOS – Team 3, Epistress, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 1, France.
ABSTRACT: Background: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. Methods: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. Findings: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. Interpretation: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. Funding: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé. Key words: Osteosarcoma, Bone tumours, MTH1, ROS, DNA damage
