title: VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations.
abstract: K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a non-invasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-ras(LA1) model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations.
authors.affiliation: a Université François Rabelais, UMR , Tours , France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Hervé
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rabbe
authors.forename: Laurent
authors.initials: L
authors.lastname: Guilleminault
authors.forename: Flora
authors.initials: F
authors.lastname: Paul
authors.forename: Laurène
authors.initials: L
authors.lastname: Schlick
authors.forename: Nicolas
authors.initials: N
authors.lastname: Azzopardi
authors.forename: Michael
authors.initials: M
authors.lastname: Duruisseaux
authors.forename: Delphine
authors.initials: D
authors.lastname: Fouquenet
authors.forename: Jérôme
authors.initials: J
authors.lastname: Montharu
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.forename: Etienne
authors.initials: E
authors.lastname: Lemarié
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heuzé-Vourc'h
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000517:prevention & control; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D042461:Vascular Endothelial Growth Factor A; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-ras mutation; Non-small cell lung cancer; aerosol; airways delivery; anti-VEGF; anti-angiogenic agent; lung adenocarcinoma; monoclonal antibody; pharmacokinetics