A High-throughput Pharmacoviral Approach Identifies Novel Oncolytic Virus Sensitizers

Abstract

Oncolytic viruses (OVs) are promising anticancer agents but like other cancer monotherapies, the genetic heterogeneity of human malignancies can lead to treatment resistance. We used a virus/cell-based assay to screen diverse chemical libraries to identify small molecules that could act in synergy with OVs to destroy tumor cells that resist viral infection. Several molecules were identified that aid in viral oncolysis, enhancing virus replication and spread as much as 1,000-fold in tumor cells. One of these molecules we named virus-sensitizers 1 (VSe1), was found to target tumor innate immune response and could enhance OV efficacy in animal tumor models and within primary human tumor explants while remaining benign to normal tissues. We believe this is the first example of a virus/cell-based "pharmacoviral" screen aimed to identify small molecules that modulate cellular response to virus infection and enhance oncolytic virotherapy.

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

“…A highthroughput screening approach 14 identified seven approved drugs that have microtubule-destabilizing activity among 15 previously unknown compounds found to enhance VSVD51-mediated oncolysis. The compounds, their drug class and structures are listed in Supplementary Table 1.…”

Virus-Activated Interferon Regulatory Factor 7 Upregulates Expression of the Interferon-Regulated BST2 Gene Independently of Interferon Signaling

“…Red fluorescence protein-tagged VSV-M⌬51 (Indiana serotype) was a gift from J. Bell (University of Ottawa, Ottawa, Canada) (11). VSV was propagated in BHK-21 cells, and titers were determined by plaque assay in the same cells (62).…”

<em>Ex Vivo</em> Infection of Live Tissue with Oncolytic Viruses

“…One key characteristic of oncolytic viruses is that they can be genetically modified to express reporter transgenes which makes it possible to visualize the infection of tissues by microscopy or bio-luminescence imaging 6,7 . This offers a unique advantage since it is possible to infect tissues from patients ex vivo prior to therapy in order to ascertain the likelihood of successful oncolytic virotherapy 8 . To this end, it is critical to appropriately sample tissue to compensate for tissue heterogeneity and assess tissue viability, particularly prior to infection 9 .…”