Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy.
OBJECTIVE
Inhibition of the vascular endothelial growth factor (VEGF) axis is the basis of all currently approved antiangiogenic therapies. In preclinical models, anti-VEGF blocking antibodies have shown broad efficacy that is dependent on both tumor context and treatment duration. We aimed to characterize this activity and to evaluate the effects of discontinuation of treatment on the dynamics of tumor regrowth.


METHODS
We evaluated the effects of anti-VEGF treatment on tumor growth and survival in 30 xenograft models and in genetic mouse models of cancer. Histologic analysis was used to evaluate the effects of treatment on tumor vasculature. We used a variety of treatment regimens to allow analysis of the effects of treatment duration and cessation on growth rate, survival, and vascular density.


RESULTS
Preclinical tumor models were characterized for their varied dependence on VEGF, thereby defining models for testing other agents that may complement or augment anti-VEGF therapy. We also found that longer exposure to anti-VEGF monoclonal antibodies delayed tumor growth and extended survival in established tumors from both cell transplants and genetic tumor models and prevented regrowth of a subset of residual tumors following cytoablative therapy. Discontinuation of anti-VEGF in established tumors resulted in regrowth at a rate slower than that in control-treated animals, with no evidence of accelerated tumor growth or rebound. However, more rapid regrowth was observed following discontinuation of certain chemotherapies. Concurrent administration of anti-VEGF seemed to normalize these accelerated growth rates.


CONCLUSIONS
In diverse preclinical models, continuous VEGF suppression provides maximal benefit as a single agent, combined with chemotherapy, or as maintenance therapy once chemotherapy has been stopped.
Bagri
Anil
A
Department of Tumor Biology and Angiogenesis, Genentech Inc., South San Francisco, CA 94080, USA. abagri@gene.com
Berry
Leanne
L
Gunter
Bert
B
Singh
Mallika
M
Kasman
Ian
I
Damico
Lisa A
LA
Xiang
Hong
H
Schmidt
Maike
M
Fuh
Germaine
G
Hollister
Beth
B
Rosen
Oliver
O
Plowman
Greg D
GD
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003429:Cross Reactions; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A