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

Brice Moukengue1, Hannah K Brown2, Céline Charrier1

  • 1Université de Nantes, INSERM, U1238, Sarcomes osseux et remodelage des tissus calcifiés, Team 3, Epistress, Rue Gaston Veil, 44035 Nantes cedex, France.

Ebiomedicine
|March 11, 2020
PubMed
Abstract

Insights

MTH1 inhibitors TH588 and TH1579 show promise for osteosarcoma treatment. TH1579 significantly reduced tumor growth and metastasis in preclinical models, offering a potential new therapy for this challenging cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Osteosarcoma (OS) is the most common primary bone cancer with a stagnant 5-year survival rate of 30% for poor responders, indicating a critical need for novel therapeutic strategies.
  • The enzyme Mutt homolog 1 (MTH1) is overexpressed in various cancers, including OS, and plays a role in preventing the incorporation of oxidized nucleotides into DNA, making it a potential therapeutic target.

Purpose of the Study:

  • To evaluate the therapeutic potential of targeting MTH1 with chemical inhibitors TH588 and TH1579 in human osteosarcoma cells.
  • To assess the preclinical efficacy of TH1579 in an in vivo osteosarcoma xenograft model, focusing on tumor growth and pulmonary metastasis reduction.

Main Methods:

  • In vitro studies involved treating human osteosarcoma cells with TH588 and TH1579 to assess effects on cell viability, cell cycle, and apoptosis.
  • In vivo efficacy of TH1579 was evaluated in an osteosarcoma xenograft model, monitoring tumor growth, pulmonary metastasis, and DNA damage markers.
  • Cellular thermal shift assay (CETSA) was used to confirm TH1579 binding to MTH1 in the osteosarcoma model.

Main Results:

  • MTH1 was found to be overexpressed in OS patients and cell lines compared to mesenchymal stem cells.
  • In vitro, TH588 and TH1579 inhibited MTH1, leading to decreased OS cell viability, impaired cell cycle progression, and increased apoptosis.
  • In vivo, TH1579 (90 mg/kg) significantly reduced tumor growth by 80.5% and decreased pulmonary metastases, correlating with increased 8-oxo-dG integration into tumor DNA and apoptosis.

Conclusions:

  • The study provides strong preclinical evidence that TH1579 is a viable therapeutic option for osteosarcoma patients.
  • Targeting MTH1 with TH1579 demonstrates significant anti-tumor activity and metastatic potential in osteosarcoma models.
  • Further clinical investigation of TH1579 for osteosarcoma treatment is warranted based on these promising preclinical findings.
Keywords:
Bone tumoursDNA damageMTH1OsteosarcomaROS

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