Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels.
Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.
Fischer
Christian
C
Department for Transgene Technology and Gene Therapy, VIB, 3000, Leuven, Belgium.
Jonckx
Bart
B
Mazzone
Massimiliano
M
Zacchigna
Serena
S
Loges
Sonja
S
Pattarini
Lucia
L
Chorianopoulos
Emmanuel
E
Liesenborghs
Laurens
L
Koch
Marta
M
De Mol
Maria
M
Autiero
Monica
M
Wyns
Sabine
S
Plaisance
Stephane
S
Moons
Lieve
L
van Rooijen
Nico
N
Giacca
Mauro
M
Stassen
Jean-Marie
JM
Dewerchin
Mieke
M
Collen
Desire
D
Carmeliet
Peter
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D064420:Drug-Related Side Effects and Adverse Reactions; D006262:Health; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2