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ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity
Tim H Holmström1, Anu-Maarit Moilanen2, Tarja Ikonen2
1Orion Corporation Orion Pharma, Finland. tim.holmstrom@orionpharma.com.
Abstract:
Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.
Insights
ODM-203, a novel inhibitor targeting both Fibroblast Growth Factor Receptor (FGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR), demonstrates potent antitumor activity. This dual-targeting approach shows promise in preclinical cancer models by inhibiting tumor growth and modulating the immune microenvironment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibroblast Growth Factor Receptor (FGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) signaling pathways are frequently altered in cancer, correlating with disease progression and poor survival.
- These pathways synergistically promote tumor angiogenesis, and FGFR activation can confer resistance to VEGFR inhibitors.
- Selective small-molecule inhibitors targeting FGFR are under clinical investigation.
Purpose of the Study:
- To characterize ODM-203, a novel, selective, and equipotent inhibitor of both FGFR and VEGFR kinase families.
- To evaluate the preclinical antitumor efficacy and immune-modulating effects of ODM-203 in various cancer models.
Main Methods:
- Biochemical and cellular assays were used to determine the inhibitory potency of ODM-203 against FGFR and VEGFR kinases.
- Antitumor activity was assessed in vivo using FGFR-dependent and angiogenesis-dependent xenograft models, as well as a syngeneic model.
- Immune modulation was analyzed by measuring checkpoint protein expression (PD-1, PD-L1) and T cell activation in the tumor microenvironment.
Main Results:
- ODM-203 demonstrated equipotent inhibition of FGFR and VEGFR family kinases in the low nanomolar range (IC50 6-35 nmol/L).
- The compound effectively inhibited VEGFR-induced angiogenesis and proliferation in FGFR-dependent cell lines.
- ODM-203 exhibited significant antitumor activity in multiple preclinical models, including xenografts and a syngeneic model, at well-tolerated doses.
- In vivo studies revealed that ODM-203's antitumor effects correlated with decreased PD-1/PD-L1 expression and enhanced CD8 T cell activation, indicating immune modulation.
Conclusions:
- ODM-203 is a potent and selective dual inhibitor of FGFR and VEGFR kinases.
- The drug displays significant antitumor efficacy in preclinical models, targeting both tumor growth and angiogenesis.
- ODM-203 possesses immunomodulatory properties, suggesting a potential role in enhancing anti-tumor immunity.
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