Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer

Wong, Carmen; Nash, Leslie A.; Papa, Joshua Del; Poulin, Kathy L.; Falls, Theresa; Bell, John C.; Parks, Robin J.

doi:10.1038/cgt.2016.41

Cited by 8 publications

(9 citation statements)

References 38 publications

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“…Expression of the p14 FAST protein by a replication-defective adenovirus vector was recently shown not to provide a therapeutic benefit in a murine cancer model. 45 However, in cella and ex vivo coinfection experiments with VSV-p14 and an oncolytic vaccinia virus showed a synergistic interaction that increased cell killing and spread of both viruses. 29 This synergistic effect was attributed to p14-induced syncytium formation enhancing cell-cell spread of the mostly cell-associated vaccinia virus, with expression of the vaccinia virus B18R gene that locally inhibits type I IFN responses promoting replication of VSV-p14.…”

Section: Discussionmentioning

confidence: 99%

Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models

Bœuf

Gebremeskel

McMullen

et al. 2017

Molecular Therapy - Oncolytics

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The reovirus fusion-associated small transmembrane (FAST) proteins are the smallest known viral fusogens (∼100–150 amino acids) and efficiently induce cell-cell fusion and syncytium formation in multiple cell types. Syncytium formation enhances cell-cell virus transmission and may also induce immunogenic cell death, a form of apoptosis that stimulates immune recognition of tumor cells. These properties suggest that FAST proteins might serve to enhance oncolytic virotherapy. The oncolytic activity of recombinant VSVΔM51 (an interferon-sensitive vesicular stomatitis virus [VSV] mutant) encoding the p14 FAST protein (VSV-p14) was compared with a similar construct encoding GFP (VSV-GFP) in cell culture and syngeneic BALB/c tumor models. Compared with VSV-GFP, VSV-p14 exhibited increased oncolytic activity against MCF-7 and 4T1 breast cancer spheroids in culture and reduced primary 4T1 breast tumor growth in vivo. VSV-p14 prolonged survival in both primary and metastatic 4T1 breast cancer models, and in a CT26 metastatic colon cancer model. As with VSV-GFP, VSV-p14 preferentially replicated in vivo in tumors and was cleared rapidly from other sites. Furthermore, VSV-p14 increased the numbers of activated splenic CD4, CD8, natural killer (NK), and natural killer T (NKT) cells, and increased the number of activated CD4 and CD8 cells in tumors. FAST proteins may therefore provide a multi-pronged approach to improving oncolytic virotherapy via syncytium formation and enhanced immune stimulation.

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Section: Discussionmentioning

confidence: 99%

Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models

Bœuf

Gebremeskel

McMullen

et al. 2017

Molecular Therapy - Oncolytics

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“…It is deleted of the E3 region. Ad(E1 -)-CMV/RFP (AdRP2619) and Ad(E1 ϩ )TP-F (AdRP3000) constructs have been described previously (17,88,89). All viruses were propagated in 293 cells and purified by cesium chloride buoyant density centrifugation using standard procedures (90).…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Saha

Parks

2019

J Virol

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Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease. IMPORTANCE Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

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“…Unfortunately, these promising in vitro results did not translate in vivo, as immunodeficient mice bearing subcutaneous A549 tumors did not show improved tumor regression or prolonged lifespan when treated with AdFAST compared to animals treated with control virus or vehicle. AdFAST was also tested in an immunocompetent, syngeneic mouse model of cancer but, unfortunately, no increase in treated mouse survival or reduction in tumor growth was observed [ 80 ]. Studies in vitro in 293 cells, in which the AdFAST virus can replicate due to complementation of the E1-deletion in this cell line, showed that extensive fusion and a decrease in metabolic activity could be achieved at a very low MOI [ 62 ].…”

Section: Expression Of Fusogenic Proteins From Replication-defectimentioning

confidence: 99%

Adenoviral Vectors Armed with Cell Fusion-Inducing Proteins as Anti-Cancer Agents

Papa

Parks

2017

Viruses

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Cancer is a devastating disease that affects millions of patients every year, and causes an enormous economic burden on the health care system and emotional burden on affected families. The first line of defense against solid tumors is usually extraction of the tumor, when possible, by surgical methods. In cases where solid tumors can not be safely removed, chemotherapy is often the first line of treatment. As metastatic cancers often become vigorously resistant to treatments, the development of novel, more potent and selective anti-cancer strategies is of great importance. Adenovirus (Ad) is the most commonly used virus in cancer clinical trials, however, regardless of the nature of the Ad-based therapeutic, complete responses to treatment remain rare. A number of pre-clinical studies have shown that, for all vector systems, viral spread throughout the tumor mass can be a major limiting factor for complete tumor elimination. By expressing exogenous cell-fusion proteins, many groups have shown improved spread of Ad-based vectors. This review summarizes the research done to examine the potency of Ad vectors expressing fusogenic proteins as anti-cancer therapeutics.

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Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer

Cited by 8 publications

References 38 publications

Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models

Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Adenoviral Vectors Armed with Cell Fusion-Inducing Proteins as Anti-Cancer Agents

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