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.

中文翻译：

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TH1579，MTH1抑制剂，可延迟肿瘤生长并抑制骨肉瘤模型的转移发展

背景

骨肉瘤（OS）是最常见的原发性恶性骨肿瘤。不幸的是，没有新的疗法被批准，并且在过去的30年中，对于较弱的应答者来说，迫切需要新疗法的存在，其5年生存率仍然只有30％。Mutt同系物1（MTH1）酶可防止氧化的核苷酸掺入DNA中，而最近开发的MTH1抑制剂可能会提供治疗潜力，因为MTH1在各种癌症中过表达。

方法

这项研究的目的是评估以两种化学抑制剂TH588和TH1579靶向MTH1对人骨肉瘤细胞的治疗益处。在人类骨肉瘤异种移植模型中评估了TH1579的临床前疗效，研究了其在肿瘤生长和肺转移中的发展。

发现

与间充质干细胞相比，MTH1在OS患者和肿瘤细胞系中过表达。在体外，TH588和TH1579对MTH1的化学抑制作用会降低OS细胞的生存能力，损害其细胞周期并增加OS细胞的凋亡。在OS模型中，CETSA证实TH1579与MTH1结合。此外，在第48天，与未治疗组相比，90 mg / kg的TH1579使体内肿瘤生长降低80.5％。该结果与8-氧代-dG整合入肿瘤细胞DNA的增加和细胞凋亡的增加有关。此外，TH1579还减少了肺转移的数量。

解释

所有这些结果有力地提供了临床前的原则证明，TH1579可以作为骨肉瘤患者的治疗选择。

资金

这项研究得到了La Ligue Contre le Cancer，la SFCE和Enfants CancersSanté的支持。