ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity

Abstract

Angiogenesis is crucial for maintaining the supply of oxygen and nutrients required to support solid tumour growth. Inhibitors of tumour blood vessel formation are therefore being sought, in particular, inhibitors of vascular endothelial growth factor-A (VEGF)-signalling, which has a pivotal role in stimulating neovascular growth and survival. ZD6474 is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumour-induced angiogenesis. Consistent with inhibition of angiogenesis, once-daily oral dosing of ZD6474 produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, ZD6474 also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. This may be particularly relevant in tumours with a dependency upon EGFR signalling, for example in certain tumours harbouring activating mutations in EGFR. RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment.

Figure 1

ZD6474 chemical structure and mechanism of action.

Figure 2

ZD6474 inhibits tumour-induced new blood vessel development. A549 tumour cells were implanted intradermally and new blood vessel formation was assessed after 5 days' administration of ZD6474 (50 or 100 mg kg⁻¹ day⁻¹) or vehicle (Wedge et al, 2002).

Figure 3

ZD6474 reduces tumour microvessel density. Intravital microscopy image taken in mice with L3.6pl pancreatic tumours growing in dorsal skin-fold chambers after 6 days' treatment with ZD6474 (50 mg kg⁻¹ day⁻¹) (Figure provided by CJ Bruns).

Figure 4

Antitumour efficacy of ZD6474 in a range of tumour types (adapted from Wedge et al, 2002).

Figure 5

Antitumour activity of ZD6474 in combination with paclitaxel on established GEO xenografts. After inoculation with GEO cells, mice were treated on days 1–5 of each week for 4 weeks with ZD6474 (100 or 150 mg kg⁻¹ day⁻¹), alone or in combination with paclitaxel (20 mg kg⁻¹ dose⁻¹) on day 1 of each week for 4 weeks (Ciardiello et al, 2003).