title: Combining virotherapy and angiotherapy for the treatment of breast cancer.
abstract: A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.
authors.affiliation: Department of Oncology, Old Road Campus, University of Oxford, Oxford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bazan-Peregrino
authors.forename: R C A
authors.initials: RC
authors.lastname: Sainson
authors.forename: R C
authors.initials: RC
authors.lastname: Carlisle
authors.forename: C
authors.initials: C
authors.lastname: Thoma
authors.forename: R A
authors.initials: RA
authors.lastname: Waters
authors.forename: C
authors.initials: C
authors.lastname: Arvanitis
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: Hernandez-Alcoceba
authors.forename: L W
authors.initials: LW
authors.lastname: Seymour
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy* / Q000821:virology; D002135:Calcium-Binding Proteins; D048708:Cell Growth Processes / Q000502:physiology; D003131:Combined Modality Therapy; D004621:Embolization, Therapeutic / Q000379:methods*; D005260:Female; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011960:Receptors, Estrogen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1