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.