Abstract LB-362: PlGF inhibition phenocopies PlGF deficiency in cancer
Authors: Schmidt Thomas , Van de Veire Sara , Heindryckx Femke , Oura Hajimu , Tijeras-Raballand Annemilaï , Loges Sonja , Albrecht Imke , Jonckx Bart , Vinckier Stefan , Van Steenkiste Christophe , Tugues Sònia , Rolny Charlotte , De Mol Maria , Dettori Daniela , Hainaud Patricia , Coenegrachts Lieve , Contreres Jean-Olivier , Cuervo Henar , Henaff Carole Le , Buysschaert Ian , Masouleh Behzad Kharabi , Geerts Anja , Schomber Tibor , Bonnin Philippe , Haustraete Juergen , Zacchigna Serena , Jiménez Wladimiro , Giacca Mauro , Colle Isabelle , Tobelem Gerard , Morales-Ruiz Manuel , Vilar José , Carmeliet Geert , Dewerchin Mieke , Claesson-Welsh Lena , Dupuy Evelyne , Van Vlierberghe Hans , Christofori Gerhard , Mazzone Massimiliano , Detmar Michael , Collen Désiré , Carmeliet Peter 
Published: February 2011

Abstract
To overcome the resistance to VEGF-inhibitor treatment, additional anti-angiogenic agents need to be valorized. Placental growth factor (PlGF), a VEGF homologue, stimulates endothelial, tumor and inflammatory cells. Studies in independently generated PlGF−/− mice by us and Regeneron identified a role for PlGF in inflammatory, ischemic and malignant disease, while the anti-PlGF mAb 5D11D4 blocks growth of implanted tumors. Several clinical studies also show that PlGF levels correlate with poor prognosis in diverse types of cancer, while the humanized anti-human PlGF mAb TB403 has been succesfully tested in a phase I trial in out-treated cancer patients. However, genetic evidence for a disease-candidate role of PlGF or an effect of the anti-PlGF mAb 5D11D4 in spontaneous cancer models has been lacking so far. Here, we show that loss of PlGF inhibited a carcinogen-induced skin tumor model papilloma formation and angiogenesis. Furthermore, silencing of PlGF in a transgenic hepatocellular carcinoma (HCC) model reduced tumor size and incidence. In a carcinogen-induced HCC model, most WT but only a minority of PlGF−/− mice died, while fewer tumor nodules developed in PlGF−/− mice. When WT mice with established HCC were treated with 5D11D4, more control IgG than 5D11D4 treated mice died. PlGF blockage inhibited the characteristic arterialization response in these tumors and blocked vessel abnormalization in HCC leading to reduced levels of hypoxia, known to stimulate HCC growth, however, without affecting microvascular density. These findings indicate that the anti-cancer activity of PlGF-blockage is not reflected by a change in vessel density alone. In the Rip1Tag2 model, no differences between WT and PlGF−/− mice or 5D11D4-treated mice in tumor burden or incidence were found, indicating that 5D11D4 does not have off-target effects. Resistance of this model is likely due to the lack of infiltration by Gr1+ neutrophils by PlGF blockage. These findings and previously published results of a Phase I trial with TB403 warrant furter analysis of anti-PlGF strategies for (non)-oncology indications.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-362.