Angiogenesis — the formation of new blood vessels — is essential for tumour progression and metastasis. Vascular endothelial growth factor (VEGF) has a key role in this process that seems to be mediated mainly by one of its receptors, KDR, which is overexpressed on the tumour vasculature. Writing in Proceedings of the National Academy of Sciences, Veenendaal et al. describe how this could be therapeutically exploited by fusing the toxin gelonin (rGel) to VEGF to selectively destroy the tumour vasculature in vivo.

The fusion protein, which consists of VEGF121 (one of at least four human VEGF isoforms) linked by a flexible tether to rGel, was expressed in Escherichia coli and purified, and shown to activate KDR in the same manner as VEGF121 alone. Gelonin was chosen as the toxin as it does not seem to be antigenic in humans, and — unlike other toxins assessed so far for antitumour therapies — it does not seem to cause damage to normal blood vessels.

In in vitro tests, VEGF121/rGel was highly toxic (IC50 ≤ 1 nm) to dividing endothelial cells that overexpressed the KDR receptor, but cells expressing lower levels of KDR were no more sensitive to VEGF121/rGel than to free rGel (IC50 ≥ 300 nm). This requirement to surpass a threshold level of KDR expression could be important for the safety of VEGF121/rGel, as the level of KDR expression on normal organs is likely to be below the threshold. Moreover, VEGF121/rGel was 60-fold more toxic to dividing cells than non-dividing cells expressing the same levels of KDR.

The promise of the in vitro results was well borne out in vivo — in mice with human-melanoma or human-prostate xenografts, treatment with VEGF121/rGel resulted in a reduction in tumour volume to <17% of the untreated controls. VEGF121/rGel was localized primarily on the vascular endothelium of the tumours, and vascular damage and thrombosis of tumour blood vessels was observed, in contrast to normal tissues, in which the vasculature seemed unaffected. Overall, it seems that selective destruction of the tumour vasculature can be achieved with VEGF121/rGel in mice, and human trials are expected to begin in the next year.