Abstract 4133: ODM-203, a novel, selective and balanced FGFR and VEGFR inhibitor with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic cancer models

Abstract

Abstract Genomic alterations in fibroblast growth factor receptors (FGFR) and upregulation of vascular endothelial growth factor receptors (VEGFR) are often found in the same cancer types such as gastric, lung and breast and these alterations correlate with patient survival and disease progression. In addition, both FGFR and VEGFR signaling promote tumor angiogenesis. Activation of FGFR signaling has also been described to function as a compensatory angiogenic signal following development of resistance to VEGF inhibition. ODM-203 is a novel and selective inhibitor of the FGFR and VEGFR families exhibiting equal potency to both receptors both in vitro and in vivo. In recombinant kinase assays, ODM-203 inhibits both the FGFR and VEGFR family kinases in the low nanomolar range (IC50 6-35 nM). In cells, ODM-203 suppresses FGFR and VEGFR signaling with similar potency. It also inhibits VEGF-induced endothelial cell (HUVEC) proliferation (IC50 33 nM) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nM). In vivo, ODM-203 shows strong anti-tumor activity in FGFR-dependent xenograft models and in angiogenic xenograft models with similar well tolerated doses. In addition ODM-203 inhibits metastatic tumor growth in angiogenic xenograft models. Lack of activity in a FGFR and VEGFR independent tumor models further supports the selective mode of action of ODM-203. Oral administration of ODM-203 was well tolerated with only FGFR or VEGFR inhibition related physiological events observed in vivo in rat and dog. Based on our findings, ODM-203 has a unique profile with equal potency for both FGFR and VEGFR kinase families which correlates with with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic tumor models. Therefore, a clinical trial with ODM-203 is ongoing in patients with solid tumors (NCT 02264418). Citation Format: Tim Holmström, Anu Moilanen, Mari Björkman, Tero Linnanen, Gerd Wohlfahrt, Stefan Karlsson, Riikka Oksala, Timo Korjamo, Susanta Samajdar, Srinivasan Rajagopalan, Shekar Chelur, Kishore Narayan, Raghuveer Ramachandra, Thomas Anthony, Samiulla DS, Murali Ramachandra, Pekka Kallio. ODM-203, a novel, selective and balanced FGFR and VEGFR inhibitor with strong activity on primary and metastatic tumor growth in FGFR-dependent and angiogenic cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4133. doi:10.1158/1538-7445.AM2015-4133