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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers
Jean-Simon Diallo1, Fabrice Le Boeuf, Frances Lai
1Ottawa Hospital Research Institute, Center for Cancer Therapeutics, Ottawa, Ontario, Canada.
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.
Insights
Researchers discovered small molecules that enhance oncolytic virus (OV) therapy. These virus-sensitizers boost OV effectiveness against resistant tumors by targeting the innate immune response, improving cancer treatment outcomes.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Drug discovery
Background:
- Cancer genetic heterogeneity leads to resistance against monotherapies like oncolytic viruses (OVs).
- Developing strategies to overcome treatment resistance is crucial for improving cancer patient outcomes.
Purpose of the Study:
- To identify small molecules that synergize with OVs to enhance tumor cell destruction.
- To discover compounds that overcome resistance to oncolytic virotherapy.
Main Methods:
- A virus/cell-based assay was employed to screen chemical libraries.
- Identified synergistic small molecules were tested for their ability to enhance viral replication and spread.
- The efficacy of lead compounds was evaluated in animal tumor models and human tumor explants.
Main Results:
- Several small molecules were identified that significantly enhance viral oncolysis, increasing virus replication and spread up to 1,000-fold.
- One identified molecule, virus-sensitizer 1 (VSe1), targets the tumor's innate immune response.
- VSe1 demonstrated enhanced OV efficacy in preclinical models without harming normal tissues.
Conclusions:
- This study presents the first virus/cell-based "pharmacoviral" screen for identifying synergistic small molecules.
- Virus-sensitizers can overcome resistance to oncolytic virotherapy by modulating cellular responses to viral infection.
- The findings offer a promising new strategy for enhancing the efficacy of oncolytic virus therapy in cancer treatment.
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