ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity
| Autor: | Shekar Chelur, Murali Ramachandra, Samiulla Dhodheri, Stefan Karlsson, Nanduri Srinivas, Thomas Anthony, Nagaraj Gowda, Kishore Narayanan, Tero Linnanen, Raghuveer Ramachandra, Tarja Ikonen, Jiju Mani, Susanta Samajdar, Ravi Kotrabasaiah Ujjinamatada, Srinivasan Rajagopalan, Timo Korjamo, Mari Björkman, Subhendu Mukherjee, Pekka Kallio, Rashmi Nair, Riikka Oksala, Gerd Wohlfahrt, Tim H. Holmström, Anu-Maarit Moilanen |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research animal structures Cell Survival T-Lymphocytes Programmed Cell Death 1 Receptor CD8-Positive T-Lymphocytes B7-H1 Antigen 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation In vivo Cell Line Tumor Cytotoxic T cell Animals Humans Phosphorylation Carcinoma Renal Cell Protein Kinase Inhibitors Cell Proliferation Tube formation Tumor microenvironment Chemistry Kinase Receptors Fibroblast Growth Factor Xenograft Model Antitumor Assays Kidney Neoplasms Killer Cells Natural 030104 developmental biology Receptors Vascular Endothelial Growth Factor Oncology Cell culture 030220 oncology & carcinogenesis embryonic structures Cancer research Syngenic |
| Zdroj: | Molecular cancer therapeutics. 18(1) |
| ISSN: | 1538-8514 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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