Careful decoy receptor titering is required to inhibit tumor angiogenesis while avoiding adversely altering VEGF bioavailability.
To inhibit tumor-induced angiogenesis, the VEGF signaling pathway was targeted using AAV vectors encoding a VEGF decoy receptor, a truncated, soluble form of the murine VEGF receptor-2 (tsFlk-1). This approach initially had significant anti-neuroblastoma efficacy in murine xenograft models of local and metastatic disease, but when higher circulating levels of tsFlk-1 were established, tumor growth was more aggressive than even in control mice. Part of the mechanism for this apparent tumor resistance was increased human VEGF expression by the tumor cells. However, further investigation revealed that although a greater amount of VEGF could be bound by higher levels of tsFlk-1, more VEGF also existed in an unbound state and was, therefore, available to support angiogenesis. This novel, tumor-independent mechanism for resistance to antiangiogenic strategies suggests that careful titering of angiogenesis inhibitors may be required to achieve maximal antitumor efficacy and avoid therapy resistance mediated, in part, by ligand bioavailability. This has important implications for therapeutic strategies that use decoy receptors and other agents, such as antibodies, to bind angiogenic factors, in an attempt to inhibit tumor neovascularization.
Davidoff
Andrew M
AM
Department of Surgery St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Ng
Catherine Y C
CY
Zhang
Youbin
Y
Streck
Christian J
CJ
Mabry
Stephanie J
SJ
Barton
Susan H
SH
Baudino
Troy
T
Zhou
Junfang
J
Kerbel
Robert S
RS
Vanin
Elio F
EF
Nathwani
Amit C
AC
D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D051379:Mice; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2