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Supplementary Table S1 and Figures S1-S7 from ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity

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journal contribution
posted on 2023-04-03, 15:10 authored by Tim H. Holmström, Anu-Maarit Moilanen, Tarja Ikonen, Mari L. Björkman, Tero Linnanen, Gerd Wohlfahrt, Stefan Karlsson, Riikka Oksala, Timo Korjamo, Susanta Samajdar, Srinivasan Rajagopalan, Shekar Chelur, Kishore Narayanan, Raghuveer K. Ramachandra, Jiju Mani, Rashmi Nair, Nagaraj Gowda, Thomas Anthony, Samiulla Dhodheri, Subhendu Mukherjee, Ravi K. Ujjinamatada, Nanduri Srinivas, Murali Ramachandra, Pekka J. Kallio

Supplementary table S1 shows the effect of ODM-203 in a large kinase panel. Supplementary figure S1 shows how ODM-203 is synthesized. Supplementary figure S2 shows the effect of ODM-203 on FRS2 phosphorylation. Supplement figure S3 shows the effect of ODM-203 in additional in vivo xenograft models. Supplement figure S4 shows the effect of ODM-203 on pFGFR in the SNU16 xenograft model. Supplement figure S5 shows the effect of ODM-203 on pFGFR in the KSM11 xenograft model. Supplement figure S6 shows the effect of ODM-203 angiogenesis in vivo. Supplement figure S7 shows the effect of ODM-203 on PD-L1 expression in vitro.

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ARTICLE 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.