Mechanism and Rational Combinations With GP-2250, a Novel Oxathiazine Derivative, in Ovarian Cancer

Authors

Mark S Kim
Deanna Glassman
Katelyn F Handley
Adrian Lankenau Ahumada
Nicholas B Jennings
Emine Bayraktar
Katherine Foster
Robiya Joseph
Sanghoon Lee
Robert L Coleman
Anil K Sood

Publication Date

8-1-2024

Journal

Cancer Medicine

Abstract

BACKGROUND: GP-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.

METHODS: We 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).

RESULTS: We 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.

CONCLUSIONS: Taken 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.

Keywords

Animals, Female, Ovarian Neoplasms, Humans, Mice, Cell Line, Tumor, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols, Drug Synergism, Apoptosis, Cell Proliferation, Antineoplastic Agents, Disease Models, Animal, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases, Poly(ADP-ribose) Polymerase Inhibitors

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Associated Data

PMID: 39114948