Preclinical rationale for FGFR1 blockade in colorectal cancer.

Abstract

164 Background: Aberrant activation of fibroblast growth factor receptor (FGFR) pathways contributes to tumor progression in colorectal cancer (CRC), often through ligand-mediated stimulation of extracellular domains. To address this, we evaluated the preclinical activity of OM-RCA-01, a humanized monoclonal antibody selectively targeting FGFR1, and compared its efficacy with bevacizumab and chemotherapy in preclinical models. Methods: For in vitro study, SW620 and HCT116 CRC cells with confirmed FGFR1 expression were exposed to OM-RCA-01, bevacizumab, or their combination at concentrations ranging from 2×10⁻⁴ to 10⁻⁷ g/ml (prepared by serial 1:2 dilutions). Following antibody treatment, cells were stimulated with FGF2 (5 ng/ml), or VEGF (10 ng/ml), or both ligands, and proliferation was quantified. For in vivo study, SW620 cells were implanted subcutaneously into the thighs of female NU–A/A Tyrc/Tyrc Foxn1nu/Foxn1nu mice. When tumors reached ~150 mm³, animals were randomized to receive: 1) OM-RCA-01 (30 mg/kg, i.p., twice weekly for 3 weeks); 2) bevacizumab (5 mg/kg, i.p., twice weekly for 3 weeks); 3) OM-RCA-01 + bevacizumab combination; 4) 5-fluorouracil (30 mg/kg, i.p., on Days 1–3 of each week for 3 weeks); 5) triple combination, or 6) saline control. Tumor dimensions were recorded every 3 days for 4 weeks. Results: In vitro, FGF2 stimulation markedly increased proliferation of both cell lines, which was dose-dependently inhibited by OM-RCA-(IC₅₀ < 25 μg/ml). Bevacizumab had no measurable effect on either FGF2- or VEGF-driven proliferation (IC₅₀ > 100 μg/ml). However, combining bevacizumab with OM-RCA-01 under dual FGF/VEGF stimulation produced a more pronounced inhibitory effect (IC₅₀ 11.2–20 μg/ml). In vivo, all treatment regimens significantly reduced tumor burden compared with saline control (Table). OM-RCA-01 monotherapy showed robust tumor suppression (P < 0.0001), with a median tumor volume of 956.7 mm³ versus 2129.9 mm³ in controls at study endpoint. The dual-antibody approach yielded tumor/control ratios (T/C) similar to either monotherapy (47.1% vs. 52.5% vs. 44.9%). Notably, the triple combination of OM-RCA-01, bevacizumab, and 5-FU demonstrated the greatest antitumor activity, achieving the smallest median tumor size (633.7 mm³; T/C = 29.8%), consistent with a synergistic interaction. Conclusions: Targeting FGFR1 effectively inhibited CRC cell proliferation and tumor progression in preclinical models. While dual FGFR1/VEGF antibody therapy did not enhance antitumor efficacy compared with single agents, the addition of chemotherapy produced a marked improvement in therapeutic activity. Tumor growth inhibition. Vehicle OM-RCA-01 Bevacizumab OM-RCA-01 + Bevacizumab 5-FU OM-RCA-01 + Bevacizumab + 5-FU Tumor volume, median, mm 3 2129.9 956.7 1117.1 1003.8 895.6 633.7 T/C% – 44.9 52.5 47.1 42.1 29.8 TGI% – 55.1 47.6 52.9 58.0 70.3