Blocking Vascular Endothelial Growth Factor-A Inhibits the Growth of Pituitary Adenomas and Lowers Serum Prolactin Level in a Mouse Model of Multiple Endocrine Neoplasia Type 1

• Published in: Clinical cancer research 2008-01, Vol.14 (1), p.249-258
• Main Authors: Korsisaari, Nina, Ross, Jed, Wu, Xiumin, Kowanetz, Marcin, Pal, Navneet, Hall, Linda, Eastham-Anderson, Jeffrey, Forrest, William F, Van Bruggen, Nicholas, Peale, Franklin V, Ferrara, Napoleone
• Format: Article
• Language: English
• Subjects: adenoma; Adenoma - blood; Adenoma - metabolism; Adenoma - pathology; angiogenesis; Animals; Antibodies, Monoclonal - pharmacology; Disease Models, Animal; endocrine; Immunohistochemistry; Magnetic Resonance Imaging; Men1; Mice; Mice, Mutant Strains; Mice, Nude; Multiple Endocrine Neoplasia Type 1 - blood; Multiple Endocrine Neoplasia Type 1 - metabolism; Multiple Endocrine Neoplasia Type 1 - pathology; Neovascularization, Pathologic; Pituitary Neoplasms - blood; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - pathology; Prolactin - blood; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - drug effects; VEGF-A
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1552

Purpose: Multiple endocrine neoplasia type 1 (MEN1) is defined clinically by the combined occurrence of multiple tumors, typically of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. A mouse model with a heterozygous deletion of the Men1 gene recapitulates the tumorigenesis of MEN1. We wished to determine the role of vascular endothelial growth factor (VEGF)-A in the vascularization and growth of MEN1-associated tumors, with an emphasis on pituitary adenomas. Experimental Design: To investigate whether tumor growth in Men1 +/− mice is mediated by VEGF-A dependent angiogenesis, we carried out a monotherapy with the anti–VEGF-A monoclonal antibody (mAb) G6-31. We evaluated tumor growth by magnetic resonance imaging and assessed vascular density in tissue sections. We also measured hormone levels in the serum. Results: During the treatment with mAb G6-31, a significant inhibition of the pituitary adenoma growth was observed, leading to an increased mean tumor doubling-free survival compared with mice treated with a control antibody. Similarly, the growth of s.c. pituitary adenoma transplants was effectively inhibited by administration of anti–VEGF-A mAb. Serum prolactin was lowered by mAb G6-31 treatment but not by control antibody, potentially providing a new therapeutic approach for treating the hormonal excess in MEN1 patients. Additionally, the vascular density in pancreatic islet tumors was significantly reduced by the treatment. Conclusions: These results suggest that VEGF-A blockade may represent a nonsurgical treatment for benign tumors of the endocrine system.