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von Hippel-Lindau Syndrome: Target for Anti-Vascular Endothelial Growth Factor (VEGF) Receptor Therapy

Imperial Cancer Research Fund, Medical Oncology Laboratories, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, England

Correspondence: Adrian L. Harris, M.D., Imperial Cancer Research Fund, Medical Oncology Laboratories, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, England. Telephone: +44-1865-222-457; Fax: +44-1865-222-431; e-mail: aharris.lab{at}icrf.icnet.uk

von Hippel-Lindau (VHL) syndrome is a familial cancer syndrome caused by germline mutations in the VHL tumor suppressor gene. Mutations in the VHL gene result in the constitutive stabilization of transcription factors hypoxia-inducible factors 1 and 2, which bind to specific enhancer elements in the vascular endothelial growth factor (VEGF) gene and stimulate angiogenesis. This increase in angiogenesis under normoxic conditions in key target organs such as the brain, kidney, and eye leads to high morbidity and reduced life expectancy. Drugs designed to block the VEGF signaling pathway may prevent the long-term complications of the disease. To test this hypothesis, a clinical study was initiated to evaluate the effect of the VEGF tyrosine kinase receptor inhibitor SU5416 in patients with VHL syndrome. Preliminary data on SU5416 indicate that it is well tolerated when administered chronically in such patients. However, since little is known about the long-term use of such inhibitors, patients will need careful monitoring. Data obtained from monitoring these patients will provide valuable information for adjuvant treatment trials in cancer patients.

Key Words. von Hippel-Lindau Syndrome • Vascular endothelial growth factor • Angiogenesis • Hypoxia-inducible factors

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