title: Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice.
abstract: Anti-VEGF-A monoclonal antibodies, in combination with chemotherapy, result in a survival benefit in patients with metastatic colorectal and non-small cell lung cancer, but little is known regarding the impact of anti-VEGF-A therapy on benign or premalignant tumors. The Apc+/min mice have been widely used as a model recapitulating early intestinal adenoma formation. To investigate whether tumor growth in Apc+/min mice is mediated by VEGF-A-dependent angiogenesis, we used two independent approaches to inhibit VEGF-A: monotherapy with a monoclonal antibody (Mab) targeting VEGF-A and genetic deletion of VEGF-A selectively in intestinal epithelial cells. Short-term (3 or 6 weeks) treatment with anti-VEGF-A Mab G6-31 resulted in a nearly complete suppression of adenoma growth throughout the small intestine. Growth inhibition by Mab G6-31 was associated with a decrease in vascular density. Long-term (up to 52 weeks) treatment with Mab G6-31 led to a substantial increase in median survival. Deletion of VEGF-A in intestinal epithelial cells of Apc+/min mice yielded a significant inhibition of tumor growth, albeit of lesser magnitude than that resulting from Mab G6-31 administration. These results establish that inhibition of VEGF-A signaling is sufficient for tumor growth cessation and confers a long-term survival benefit in an intestinal adenoma model. Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas.
authors.affiliation: Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Korsisaari
authors.forename: Ian M
authors.initials: IM
authors.lastname: Kasman
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Navneet
authors.initials: N
authors.lastname: Pal
authors.forename: Wei
authors.initials: W
authors.lastname: Bai
authors.forename: Germaine
authors.initials: G
authors.lastname: Fuh
authors.forename: Franklin V
authors.initials: FV
authors.lastname: Peale
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
mesh_terms: D000236:Adenoma / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017353:Gene Deletion; D017491:Genes, APC / Q000502:physiology*; D017403:In Situ Hybridization; D007414:Intestinal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology; D016019:Survival Analysis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A