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

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 Sant e.

OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

“…2 ). This explanation is logically more consistent than the idea that extant and unprocessed genomic 8-oxo-dG is the source of MTH1 inhibition-induced cytotoxicity, as has been previously suggested [ [9] , [10] , [11] , [12] ]. Our findings point to robust OGG1, and more generally robust BER activity, as an important determinant for tumor suppression arising from MTH1 inhibition.…”

“…The first-in-class MTH1 inhibitors, TH588 and TH287, have been shown to also produce DNA double strand break (53BP1) foci [ 8 ]. However in subsequent studies, the cytotoxicity of these inhibitors as well as their best-in-class derivative, TH1579 (karonudib) [ 9 ], has been attributed to their enhanced genomic 8-oxo-dG incorporation [ [9] , [10] , [11] , [12] ], as significant enhancement of DNA breaks relative to control conditions are observed only if recombinant OGG1 is added to the treated cells during the comet assay. However, a body of in vitro and in vivo work has shown that genomic 8-oxo-dG, in and of itself, is not a genotoxic lesion but instead a mildly mutagenic one [ 13 ].…”

Role of the NUDT Enzymes in Breast Cancer

“…The NUDT family of enzymes is an intriguing family of enzymes that play a key role in the progression of breast and other cancers. The therapeutic potential of NUDT-selective inhibitors has already been shown—NUDT1-selective inhibitors have shown efficacy in multiple studies in vitro and in vivo [ 67 , 68 , 69 , 70 ], and the NUDT5-selective inhibitor TH1457 blocks cell proliferation in breast cancer cells [ 71 ]. Given the interest in NUDT inhibition for the management of cancer patients, a greater understanding of the signaling pathways impinging on the activity of NUDT enzymes is required and may be facilitated by the interrogation of global phosphoproteomic and gene expression datasets ( Figure 4 ).…”

miR-140 inhibits osteosarcoma progression by impairing USP22-mediated LSD1 stabilization and promoting p21 expression

“…2 As such, the 5-year survival rate is roughly 30%, underscoring the urgent need for new therapies. 3 Proliferation, apoptosis, angiogenesis, tumor microenvironment, migration, and invasion are all factors that regulate the progression of malignant cancers, including osteosarcoma. 4 Therefore, the identification of mechanisms involved in osteosarcoma cell migration and invasion could lead to the development of novel therapeutic strategies used for the treatment of the disease.…”