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.
Highlights
Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer
Phosphorylation of activated β-adrenergic receptor (β-AR) by G protein-coupled receptor kinases (GRKs) leads to recruitment of the regulatory proteins, β-arrestin 1 and βarrestin 2, which control adrenergic signalling by terminating G protein activation. β-arrestins function as essential scaffold proteins, regulating diverse intracellular signalling networks[26] such as mitogen-activated protein kinases (MAPK) cascades including ERK1/227,28, as well as phosphoinositol kinase (PI3K) and Akt[26]
Our work demonstrates that β-arrestin-targeted therapies such as carvedilol can significantly improve the activity of oncolytic adenoviruses
Summary
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, dl[922-947]. As with many solid cancers, there is an urgent and unmet clinical need for new therapeutic approaches These viruses replicate selectively within cells with matched genetic defects causing cell death and dissemination of virions to neighbouring cells[4,5]. In order to facilitate clinical implementation of dl[922‐947] and other oncolytic viruses, we utilised a compound library screen to identify existing drugs that could enhance oncolytic adenoviral activity. Using this approach, we identified the β-adrenergic receptor (β-AR) antagonist, carvedilol. Β -arrestins have been shown to modulate inflammation via NFκB29,30
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