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Updated: Jun 17, 2025
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer
Mark S Kim1, Deanna Glassman1, Katelyn F Handley1,2,3
1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
GP-2250, a novel anti-neoplastic drug, effectively targets tumor metabolism by inhibiting key pathways like AKT and mTOR. Combination therapy with PARP inhibitors or bevacizumab demonstrates significant anti-tumor efficacy in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- GP-2250 is a novel analog of taurultam (TRLT) with potent anti-neoplastic properties.
- The precise mechanisms of action for GP-2250 remain largely uncharacterized.
- This study aimed to elucidate the biological effects and mechanism of action of GP-2250.
Purpose of the Study:
- To investigate the anti-cancer mechanism of GP-2250.
- To evaluate the synergistic effects of GP-2250 in combination with standard therapies.
- To assess the in vitro and in vivo efficacy of GP-2250.
Main Methods:
- In vitro assays included MTT, Annexin V/PI, colony formation, RPPA, and HRLC/IC analysis.
- In vivo studies evaluated therapeutic efficacy alone and in combination with paclitaxel, cisplatin, topotecan, and PARP inhibitors.
- Pharmacodynamic and tumor efficacy studies were conducted in ovarian cancer models.
Main Results:
- GP-2250 demonstrated synergistic effects with PARP inhibitors in ovarian cancer cell lines.
- GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mTOR signaling pathways.
- GP-2250 reduced glycolysis, ATP synthesis, and hexokinase2 activity, leading to significant tumor reduction in vivo when combined with PARP inhibitors or bevacizumab.
Conclusions:
- GP-2250 significantly impacts tumor metabolism and demonstrates potent anti-tumor activity.
- Combination therapy of GP-2250 with PARP inhibitors or bevacizumab shows promising therapeutic potential.
- These findings support the clinical development of GP-2250 for cancer treatment.
