Reference Detail

Ref Type

Journal Article

PMID

(30301864)

Authors

Holmström TH, Moilanen AM, Ikonen T, Björkman ML, Linnanen T, Wohlfahrt G, Karlsson S, Oksala R, Korjamo T, Samajdar S, Rajagopalan S, Chelur S, Narayanan K, Ramachandra RK, Mani J, Nair R, Gowda N, Anthony T, Dhodheri S, Mukherjee S, Ujjinamatada RK, Srinivas N, Ramachandra M, Kallio PJ

Title

ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	18	1	2019 Jan	28-38	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ODM-203	ODM-203	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ODM-203		ODM203\|ODM 203	FGFR Inhibitor (Pan) 26 VEGFR Inhibitor (Pan) 36	ODM-203 inhibits FGFR and VEGFR family members, potentially resulting in decreased tumor cell proliferation and decreased tumor growth (PMID: 30301864).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 amp	stomach cancer	sensitive	ODM-203	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ODM-203 inhibited FGFR signaling and proliferation in a gastric cancer cell line with amplification of FGFR2, and inhibited tumor growth in xenograft models (PMID: 30301864).	30301864
FGFR1 amp	lung large cell carcinoma	sensitive	ODM-203	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ODM-203 inhibited FGFR signaling and proliferation in a large cell lung cancer cell line with amplification of chromosome 8p12 leading to increased FGFR1 copy number, and inhibited tumor growth in xenograft models (PMID: 30301864).	30301864