Oncolytic Vesicular Stomatitis Virus Induces Apoptosis in U87 Glioblastoma Cells by a Type II Death Receptor Mechanism and Induces Cell Death and Tumor Clearance In Vivo

Cary, Zachary Dylan; Willingham, Mark C.; Lyles, Douglas S.

doi:10.1128/jvi.02393-10

Cited by 45 publications

(44 citation statements)

References 55 publications

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“…As VSV has been shown to cause cell death by apoptosis via either the intrinsic or extrinsic pathway or both (10,22,23,62), cell lines with decreased expression or activation of certain apoptotic proteins have the potential to limit/delay cell death following VSV infection. Furthermore, differences in oncolytic potential between VSV variants could be due to differences in their mechanisms of cell death induction.…”

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confidence: 99%

“…Vesicular stomatitis virus (VSV) is a promising OV and has demonstrated preclinical success against a variety of malignancies, including prostate cancer (1,11,49), breast cancer (3,20,53,63), melanoma (20,24), colorectal cancer (16,32,64), liver cancer (4)(5)75), glioblastoma (10,56,73), and other cancers (6). As a result, at least two VSV OVs have been considered for clinical trials by the NIH Recombinant-DNA Advisory Committee (10).…”

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confidence: 99%

“…As a result, at least two VSV OVs have been considered for clinical trials by the NIH Recombinant-DNA Advisory Committee (10). However, VSV's oncolytic potential has never been studied in any pancreatic cancer models.…”

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confidence: 99%

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Vesicular Stomatitis Virus as an Oncolytic Agent against Pancreatic Ductal Adenocarcinoma

Murphy

Besmer

Moerdyk-Schauwecker

et al. 2012

J Virol

108

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bVesicular stomatitis virus (VSV) is a promising oncolytic agent against a variety of cancers. However, it has never been tested in any pancreatic cancer model. Pancreatic ductal adenocarcinoma (PDA) is the most common and aggressive form of pancreatic cancer. In this study, the oncolytic potentials of several VSV variants were analyzed in a panel of 13 clinically relevant human PDA cell lines and compared to conditionally replicative adenoviruses (CRAds), Sendai virus and respiratory syncytial virus. VSV variants showed oncolytic abilities superior to those of other viruses, and some cell lines that exhibited resistance to other viruses were successfully killed by VSV. However, PDA cells were highly heterogeneous in their susceptibility to virus-induced oncolysis, and several cell lines were resistant to all tested viruses. Resistant cells showed low levels of very early VSV RNA synthesis, indicating possible defects at initial stages of infection. In addition, unlike permissive PDA cell lines, most of the resistant cell lines were able to both produce and respond to interferon, suggesting that intact type I interferon responses contributed to their resistance phenotype. Four cell lines that varied in their permissiveness to VSV-⌬M51 and CRAd dl1520 were tested in mice, and the in vivo results closely mimicked those in vitro. While our results demonstrate that VSV is a promising oncolytic agent against PDA, further studies are needed to better understand the molecular mechanisms of resistance of some PDAs to oncolytic virotherapy.

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Section: Fig 12mentioning

confidence: 99%

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confidence: 99%

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Vesicular Stomatitis Virus as an Oncolytic Agent against Pancreatic Ductal Adenocarcinoma

Murphy

Besmer

Moerdyk-Schauwecker

et al. 2012

J Virol

108

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“…U87 [100] VSV-M51R VSV M51R Nude, s.c. U87 [101] VSV-rp30 VSV P mut , L mut (VSVwt serial passage) SCID, i.c. U87 [178] srVSV VSV VSV-ΔL + VSVΔG SCID, s.c. G62 [104] Abbreviations:Ad, adenovirus; BDD, γ34.5 beclin-1 binding domain; CEA, carcinoembryonic antigen; CD, cytosine deaminase; EGFR, epidermal growth factor receptor; GBM, glioblastoma; GSC, glioblastoma stem cells; HA, hemagglutinin; HRV2, human rhinovirus type 2; HSV, herpes simplex virus; i.c., intracranial; IRES, internal ribosomal entry site; MV, measles virus; NDV, Newcastle disease virus; NIS, sodium iodide symporter; PNP, purine nucleoside phosphorylase; PV, poliovirus; PVS-RIPO, recombinant poliovirus; RCR, replication competent retrovirus; s.c., subcutaneous; TK, thymidine kinase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VGF, vaccinia growth factor; VSV, vesicular stomatitis virus; VV, vaccinia virus.…”

Section: Ad5mentioning

confidence: 99%

Current Status of Gene Therapy for Brain Tumors∗

Ning

Rabkin

2015

Translating Gene Therapy to the Clinic

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Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

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“…As a result, they are more susceptible than their normal cellular counterparts to infection and apoptotic death induced by cytopathic viruses (6,7). Vesicular stomatitis virus (VSV), a negative-strand RNA virus of the family Rhabdoviridae, is being investigated as an oncolytic agent for the treatment of prostate (6,8), skin (9,10), colorectal (2,11,12), pancreatic (13), brain (14,15), and other cancers. A variety of attenuated VSV strains have been engineered to express heterologous genes to increase selectivity for tumor cells, to augment tumor cell killing, or to enhance antitumor immunity (reviewed in reference 16).…”

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Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

Westcott

Liu

Rajani

et al. 2015

J Virol

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Oncolytic viruses (OV IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-␣2a and IFN-␤, in protection from oncolytic vesicular stomatitis virus. We found that IFN-␣2a was significantly less protective for cancer cells than was IFN-␤, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-␣2a. T he use of viruses to selectively kill cancer cells (oncolytic virotherapy) is a promising alternative therapy for cancer (1). The basis for this treatment approach is that cancer cells frequently have defective antiviral responses that develop as a consequence of cellular transformation (2-5). As a result, they are more susceptible than their normal cellular counterparts to infection and apoptotic death induced by cytopathic viruses (6, 7). Vesicular stomatitis virus (VSV), a negative-strand RNA virus of the family Rhabdoviridae, is being investigated as an oncolytic agent for the treatment of prostate (6, 8), skin (9, 10), colorectal (2, 11, 12), pancreatic (13), brain (14, 15), and other cancers. A variety of attenuated VSV strains have been engineered to express heterologous genes to increase selectivity for tumor cells, to augment tumor cell killing, or to enhance antitumor immunity (reviewed in reference 16). Recombinant VSV strains have produced encouraging preclinical results for a broad range of tumor types (17-22), and VSV expressing the human beta interferon (IFN-␤) gene currently is undergoing a phase I clinical trial for the treatment of hepatocellular carcinoma (http://www.clinicaltrials.gov/ct2/show /study/NCT01628640).Because normal cells respond to viral infection by mounting a protective type I IFN response while many cancer cells do not share this capability (7), the selectivity of VSV for cancer cells has been improved by combination treatment with type I IFN, for example, by incorporating the gene for IFN-␤ into the VSV genome or by the use of mutant or engineered VSV strains that induce robust IFN production (2, 6, 18). Wild-type VSV inhibits host antiviral responses by globally suppressing host-directed gene expression due to the activity of the viral matrix (M) protein (2,(23)(24)(25). M protein mutant strains of VSV, such as M51R VSV, are severely defective for inhibition of the host antiviral response

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Oncolytic Vesicular Stomatitis Virus Induces Apoptosis in U87 Glioblastoma Cells by a Type II Death Receptor Mechanism and Induces Cell Death and Tumor Clearance In Vivo

Abstract: Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM),

Cited by 45 publications

References 55 publications

Vesicular Stomatitis Virus as an Oncolytic Agent against Pancreatic Ductal Adenocarcinoma

Vesicular Stomatitis Virus as an Oncolytic Agent against Pancreatic Ductal Adenocarcinoma

Current Status of Gene Therapy for Brain Tumors∗

Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

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