BUDAPEST, HUNGARY — Topical or oral antiangiogenic therapy may offer a novel avenue of treatment in inflammatory skin diseases such as psoriasis and rosacea.
In what he described as the first proof-of-concept study to show that blocking the vascular endothelial growth factor (VEGF) receptor may provide an entirely new approach to treating chronic inflammatory skin conditions, Dr. Michael Detmar presented highlights of his research during a satellite symposium held in conjunction with the annual meeting of the European Society for Dermatological Research.
Antiangiogenesis therapy is a hot research area in oncology, as exemplified by the clinical and commercial success of bevacizumab (Avastin), a monoclonal antibody directed against VEGF-A signaling, but this approach has received surprisingly little attention for the treatment of chronic inflammatory skin diseases, noted Dr. Detmar, professor of pharmacogenomics and chair of the Institute of Pharmaceutical Sciences at the Swiss Federal Institute of Technology Zurich.
In studying potential dermatologic applications of VEGF inhibition, Dr. Detmar and his colleagues at the Swiss institute and Novartis opted to eschew the monoclonal antibodies favored in oncology, selecting instead a Novartis small-molecule VEGF receptor tyrosine-kinase inhibitor, NVP-BAW2881.
The production costs for a small molecule are vastly less than for biologic monoclonal antibodies, and the small molecule can be formulated as an oral or topical agent, noted Dr. Detmar.
Using a realistic transgenic mouse model of psoriasis, the investigators showed that topical application of NVP-BAW2881 addressed all three major inflammatory components of psoriasis pathogenesis: It inhibited leukocyte infiltration into the skin, reduced the abnormally large number of cutaneous blood and lymphatic vessels, and normalized epithelial architecture, curbing the keratinocyte hyperproliferation and abnormal differentiation. In effect, the VEGF receptor tyrosine kinase inhibitor essentially resolved the psoriatic phenotype, said Dr. Detmar.
In other studies using domestic pig skin, the topical agent reduced VEGF-A–induced vascular permeability, and it inhibited contact hypersensitivity reactions and UVB-induced inflammation.
“We know the lymphatic vessels are activated in inflammation,” Dr. Detmar said. “They are greatly enlarged in psoriasis and in mouse models of various chronic inflammatory conditions. The question is, what is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?”
His initial hypothesis was that lymphatic vessels promote inflammation. He and his coinvestigators put this notion to the test in laboratory mice by inhibiting lymphatic vessel function via blockade of VEGF receptor-3. This resulted in enhanced inflammation. Their hypothesis was wrong.
More recently, the investigators demonstrated that stimulation of the lymphatic vessels by chronic activation of the pathway involving VEGF receptor-3 resulted in greatly reduced skin inflammation. The mice did not develop the chronic severe psoriasislike disease for which they were genetically programmed (J. Invest. Dermatol. 2009;129:1292–8).
The satellite symposium was sponsored by Galderma SA.
Dr. Detmar reported no financial conflicts of interest in connection with his work.
'What is the role of the lymphatic vessels in skin inflammation: Do they promote it, or do they try to inhibit it?'
Source DR. DETMAR