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EBioMedicine. 2020 Mar;53:102704. doi: 10.1016/j.ebiom.2020.102704. Epub 2020 Mar 7.

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model.

Author information

1
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France.
2
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.
3
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.
4
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden.
5
Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
6
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.
7
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.
8
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.
9
Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France. Electronic address: francois.lamoureux@univ-nantes.fr.

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.

KEYWORDS:

Bone tumours; DNA damage; MTH1; Osteosarcoma; ROS

Conflict of interest statement

Declaration of Competing Interest Helleday, T: A patent has been filed with TH588 and TH1579 where T.H., is listed as inventor. The Intellectual Property Right is owned by the non-profit Thomas Helleday Foundation for Medical Research (THF). T.H. and U.W.B are board members of the THF. U.W.B is chairman of Oxcia AB. THF is sponsor for on-going clinical trial with TH1579.

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