Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor.
Genetic instability of cancer cells generates resistance after initial responses to chemotherapeutic agents. Several oncolytic viruses have been designed to exploit specific signatures of cancer cells, such as important surface markers or pivotal signaling pathways for selective replication. It is less likely for cancer cells to develop resistance given that mutations in these cancer signatures would negatively impact tumor growth and survival. However, as oncolytic viral vectors are large particles, they suffer from inefficient extravasation from tumor blood vessels. Their ability to reach cancer cells is an important consideration in achieving specific oncolytic targeting and potential vector replication. Our previous studies indicated that the Sindbis viral vectors target tumor cells by the laminin receptor. Here, we present evidence that modulating tumor vascular leakiness, using VEGF and/or metronomic chemotherapy regimens, significantly enhances tumor vascular permeability and directly enhances oncolytic Sindbis vector targeting in tumor models. Because host-derived vascular endothelium cells are genetically stable and less likely to develop resistance to chemotherapeutics, a combined metronomic chemotherapeutics and oncolytic vector regimen should provide a new approach for cancer therapy. This mechanism could explain the synergistic treatment outcomes observed in clinical trials of combined therapies.
Tseng
J-C
JC
NYU Cancer Institute and the NYU Gene Therapy Center, Department of Pathology, NYU School of Medicine, New York University, New York, NY 10016, USA.
Granot
T
T
DiGiacomo
V
V
Levin
B
B
Meruelo
D
D
D018354:Alphavirus Infections / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D015153:Blotting, Western; D002463:Cell Membrane Permeability; D003131:Combined Modality Therapy; D006224:Cricetinae; D016503:Drug Delivery Systems; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009447:Neuroblastoma / Q000098:blood supply / Q000628:therapy / Q000821:virology; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000628:therapy* / Q000821:virology; D017239:Paclitaxel / Q000627:therapeutic use; D012845:Sindbis Virus / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel