Labeling of VEGFR1D2 through oxime ligation.

We reported an useful protocol for the labeling of the second domain of the Vascular Endothelial Growth Factor Receptor 1 (VEGFR1D2), a small protein ligand able to bind VEGF, the main regulator of angiogenesis. We developed a bioconjugation strategy based on the use of oxime-ligation reaction conjugating an aldehyde derivative of the VEGFR1D2 to a molecular probe harboring an alkoxyamine functional group. We applied the synthetic protocol to prepare a biotinylated conjugate of VEGFR1D2 and we demonstrate that the bioconjugate retains its ability to specifically bind its natural ligand, VEGF, with high affinity. The biotinylated VEGFR1D2 could be useful to detect and quantify VEGF for diagnostic purposes as well as a tool for the screening of new molecules targeting VEGFRs for therapeutic applications. The labeling protocol is versatile and can be extended to different molecular probes, such as fluorophores, chelators or multimeric scaffolds, affording a biomedical platform for VEGF targeting.

Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial.

BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (≥65; ≥70 and ≥75 years). RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were ≥65 years; 29 were ≥70; 9 were ≥75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade ≥3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients ≥75 years and grade ≥3 fatigue (31% vs 20%, p=0.01) in patients <75 years. CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade ≥3 diarrhoea and neutropaenia in patients ≥75 years and grade ≥3 fatigue in patients <75 years. TRIAL REGISTRATION NUMBER: 2009-014041-81.