Smac mimetics and innate immune stimuli synergize to promote tumor death

Beug, Shawn T.; Tang, Vera A.; LaCasse, Eric C.; Cheung, Herman H.; Beauregard, Caroline E.; Brun, J; Nuyens, Jeffrey P; Earl, N.; St-Jean, Martin; Holbrook, Janelle; Dastidar, Himika; Mahoney, Douglas J.; Ilkow, Carolina S.; Bœuf, Fabrice Le; Bell, John C.; Korneluk, Robert G.

doi:10.1038/nbt.2806

Cited by 115 publications

(138 citation statements)

References 47 publications

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“…Elucidation of molecular details of oncolytic agents could provide a breakthrough in the development of therapeutic strategies combining oncolytic viruses with small molecules. Some chemovirus combination therapies have been reported, including that histone deacetylase (HDAC) inhibitors enhance oncolysis of HSV or VSV by suppressing innate immunity (40), inositolrequiring enzyme 1 (IRE1-α) inhibitors boost oncolytic efficacy of Maraba virus by inhibiting the ER stress response (41), and Smac mimetic compounds promote antitumor efficacy of VSV by exploiting the virus-stimulating cytokine storm (42). Understanding the molecular biology of M1-induced ER stress and subsequent cell death will help us to discover synergic compounds for combination therapy, such as IRE1-α inhibitors inducing ER stress (41).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Lin¹,

Zhang²,

Liang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

121

118

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Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Lin¹,

Zhang²,

Liang³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

121

118

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“…This mechanism is a newly identified method of tumor killing by the combination of vesicular stomatitis virus (VSV) and chemical agents (43). Combination of SMCs with M1 shows a tumorkilling mechanism (bystander killing) similar to the combination of SMCs and VSV, except that SMCs increase the replication of M1 but not VSV.…”

Section: Discussionmentioning

confidence: 99%

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Cai

Lin

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress-and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.oncolytic virus | SMAC mimetics | bystander killing effect

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“…This typically leads to an antiviral state in surrounding cells, but can also result in killing of uninfected tumor cells by cytokines such as tumor necrosis factor alpha (TNFα) [86]. Innate immune effectors encompass natural killer (NK) cells, which are able to induce lysis of tumor cells or virally infected cells (reviewed in [87]), and phagocytic cells such as neutrophils and macrophages.…”

Section: Modes Of Action In Oncolytic Virotherapymentioning

confidence: 99%

Fighting Cancer with Mathematics and Viruses

Santiago¹,

Heidbuechel²,

Kandell³

et al. 2017

Preprint

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After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.

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Smac mimetics and innate immune stimuli synergize to promote tumor death

Cited by 115 publications

References 47 publications

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

Fighting Cancer with Mathematics and Viruses

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