Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models.
The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.
ImClone Systems, New York, NY 10016, USA.
Inga J
IJ
Duignan
Erik
E
Corcoran
Anthony
A
Pennello
Mary Jane
MJ
Plym
Michael
M
Amatulli
Nidia
N
Claros
Michelle
M
Iacolina
Hagop
H
Youssoufian
Larry
L
Witte
Selda
S
Samakoglu
Jonathan
J
Schwartz
David
D
Surguladze
James R
JR
Tonra
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D000077210:Sunitinib; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C511761:DC101 monoclonal antibody; D051793:Hypoxia-Inducible Factor 1; D007211:Indoles; D011758:Pyrroles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib
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