Cancer gene therapy with iCaspase-9 transcriptionally targeted to tumor endothelial cells.
Antiangiogenic therapies have shown varying results partly because each tumor type secretes a distinct panel of angiogenic factors to sustain its own microvascular network. In addition, recent evidence demonstrated that tumors develop resistance to antiangiogenic therapy by turning on alternate angiogenic pathways when one pathway is therapeutically inhibited. Here, we test the hypothesis that expression of a caspase-based artificial death switch in tumor-associated endothelial cells will disrupt tumor blood vessels and slow down tumor progression irrespective of tumor type. Adenoviral vectors expressing inducible Caspase-9 (iCaspase-9) under transcriptional regulation with the endothelial cell-specific vascular endothelial growth factor receptor-2 (VEGFR2) promoter (Ad-hVEGFR2-iCaspase-9) induced apoptosis of proliferating human dermal microvascular endothelial cells (HDMECs), but not human tumor cells (UM-SCC-17B, head and neck squamous cell carcinoma; HepG2, hepatocellular carcinoma; PC-3, prostate adenocarcinoma; SLK, Kaposi's sarcoma; MCF-7, breast adenocarcinoma). Notably, apoptosis was dependent upon activation of iCaspase-9 with the dimerizer drug AP20187. Local delivery of Ad-hVEGFR2-iCaspase-9 followed by intraperitoneal injection of AP20187 ablated tumor microvessels and inhibited xenografted tumor growth in all tumor models evaluated here. We conclude that a cancer gene therapy strategy based on a transcriptionally targeted viral vector expressing an inducible caspase allows for selective and controlled ablation of microvessels of histopathologically diverse tumor types.
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
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Song
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Dong
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Jin
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Mantellini
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Núñez
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Nör
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C463061:AP20187; D040301:Vascular Endothelial Growth Factor Receptor-2; D053453:Caspase 9; D016559:Tacrolimus