ArticleCancer medicine2024
Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.
Article in Cancer medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03854110 (A Phase 1 Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Misetionamide), which is not on this map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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A Phase 1 Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Misetionamide (GP-2250) as Monotherapy or in Combination With Gemcitabine in Subjects With Advanced Solid Tumors
Who cites it
1 citing paper in PubMed.
- Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.Cancer medicine · 2024Article
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11 authors.
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Abstract
backgroundGP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models.
methodsWe carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors).
resultsWe investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups.
conclusionsTaken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.
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