Anti-angiogenic therapy increases intratumoral adenovirus distribution by inducing collagen degradation.
Conditionally replicating adenoviruses (CRAd) are a promising class of gene therapy agents that can overcome already known glioblastoma (GBM) resistance mechanisms but have limited distribution upon direct intratumoral (i.t.) injection. Collagen bundles in the extracellular matrix (ECM) have an important role in inhibiting virus distribution. In fact, ECM pre-treatment with collagenases improves virus distributions to tumor cells. Matrix metalloproteinases (MMPs) are an endogenous class of collagenases secreted by tumor cells whose function can be altered by different drugs including anti-angiogenic agents, such as bevacizumab. In this study we hypothesized that upregulation of MMP activity during anti-angiogenic therapy can improve CRAd-S-pk7 distribution in GBM. We find that MMP-2 activity in human U251 GBM xenografts increases (*P=0.03) and collagen IV content decreases (*P=0.01) during vascular endothelial growth factor (VEGF-A) antibody neutralization. After proving that collagen IV inhibits CRAd-S-pk7 distribution in U251 xenografts (Spearman rho=-0.38; **P=0.003), we show that VEGF-blocking antibody treatment followed by CRAd-S-pk7 i.t. injection reduces U251 tumor growth more than each individual agent alone (***P<0.0001). Our data propose a novel approach to improve virus distribution in tumors by relying on the early effects of anti-angiogenic therapy.
The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA.
B
B
Thaci
I V
IV
Ulasov
A U
AU
Ahmed
S D
SD
Ferguson
Y
Y
Han
M S
MS
Lesniak
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D015552:Injections, Intralesional; D053208:Kaplan-Meier Estimate; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D011107:Polylysine / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D059748:Proteolysis; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D019138:Antibodies, Blocking; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D011107:Polylysine; D003094:Collagen; D020778:Matrix Metalloproteinase 2