Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy
Joseph I Hoare1, Bleona Osmani1, Emily A O'Sullivan1
1Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Abstract:
Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment.
Insights
Carvedilol, a beta-blocker, enhances oncolytic adenovirus therapy for ovarian cancer by boosting viral replication and tumor clearance through beta-arrestin pathways. This drug repurposing improves immune response for better cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Drug repurposing
- Cancer immunology
Background:
- Oncolytic adenoviruses show promise in clinical trials for ovarian cancer.
- Enhancing oncolytic virus efficacy is crucial for improved patient outcomes.
Purpose of the Study:
- To identify existing drugs that can potentiate the activity of oncolytic adenoviruses.
- To investigate the mechanism by which carvedilol enhances oncolytic adenovirus efficacy.
Main Methods:
- Drug repurposing screen to identify synergistic compounds.
- In vitro studies using wild-type and E1A-CR2-deleted oncolytic adenoviruses.
- β-arrestin dependency confirmed via CRISPR gene editing.
- In vivo efficacy studies in orthotopic murine models of ovarian cancer.
Main Results:
- Carvedilol synergizes with oncolytic adenoviruses, independent of β-adrenergic blockade, via β-arrestins.
- Co-treatment increases viral DNA replication, protein expression, and infectious viral particle production.
- Carvedilol enhances viral tumor clearance in murine models, associated with increased inflammatory infiltrate and cytokine release.
Conclusions:
- Carvedilol augments oncolytic adenovirus activity through β-arrestins, modulating cytokine networks and innate immunity.
- This synergistic approach holds potential for improving oncolytic virus-based cancer therapies.
- Carvedilol represents a promising candidate for combination therapy in ovarian cancer treatment.
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